The DOI matches its Crossref record; 69 of the 71 references it cites were found in a registry or an index; none of the 39 sources its claims cite is checked for support yet.
Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension
Open accessAbstract
Hypertension is a leading risk factor for dementia, but the mechanisms underlying its damaging effects on the brain are poorly understood. Due to a lack of energy reserves, the brain relies on continuous delivery of blood flow to its active regions in accordance with their dynamic metabolic needs. Hypertension disrupts these vital regulatory mechanisms, leading to the neuronal dysfunction and damage underlying cognitive impairment. Elucidating the cellular bases of these impairments is essential for developing new therapies. Perivascular macrophages (PVMs) represent a distinct population of resident brain macrophages that serves key homeostatic roles but also has the potential to generate large amounts of reactive oxygen species (ROS). Here, we report that PVMs are critical in driving the alterations in neurovascular regulation and attendant cognitive impairment in mouse models of hypertension. This effect was mediated by an increase in blood-brain barrier permeability that allowed angiotensin II to enter the perivascular space and activate angiotensin type 1 receptors in PVMs, leading to production of ROS through the superoxide-producing enzyme NOX2. These findings unveil a pathogenic role of PVMs in the neurovascular and cognitive dysfunction associated with hypertension and identify these cells as a putative therapeutic target for diseases associated with cerebrovascular oxidative stress.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
Perivascular macrophages (PVMs) are required for the neurovascular and cognitive dysfunction caused by hypertension in mouse models. Circulating angiotensin II reaches the perivascular space after blood-brain barrier opening, activates PVM AT1 receptors, and drives NOX2-dependent reactive oxygen species production.
Key findings
- In slow-pressor ANGII hypertension, chronic ANGII infusion increased BBB permeability to sodium fluorescein and FITC-dextran but not Evans blue, and nearly 60% of PVMs were associated with biotinylated ANGII after 14 days; acute ANGII did not produce this BBB effect.
- Intracerebroventricular clodronate depleted PVMs by 60%–65%, did not alter blood pressure, and restored neurovascular coupling and endothelium-dependent CBF responses in ANGII-treated mice; it also rescued CBF dysfunction in chronically hypertensive BPH/2J mice.
- Bone marrow chimeras showed that AT1R or NOX2 deletion in PVMs attenuated ANGII-induced vascular oxidative stress and neurovascular dysfunction; by 14 weeks after transplant, 78% ± 2% of CD206+ cells were replaced by donor cells, and At1r−/−→WT chimerism was greater than 95%.
- PVM depletion improved cognitive deficits in BPH/2J mice: it rescued novel object recognition memory and improved Barnes maze spatial memory, while not affecting normotensive controls.
Methods
- Male C57BL/6 mice, male BPH/2J mice, and BPN/3J controls were used; hypertension was induced by osmotic minipumps delivering ANGII at 600 ng/kg/min for 2 weeks, and PVMs were depleted with intracerebroventricular liposome-encapsulated clodronate.
- Bone marrow chimeras were generated by irradiating mice and transplanting At1r−/−, Nox2−/−, or GFP+ marrow; cerebrovascular function was assessed by laser-Doppler CBF responses to whisker stimulation, acetylcholine, and adenosine, with BBB permeability measured using sodium fluorescein, FITC-dextran, and Evans blue.
- Vascular oxidative stress was assessed by hydroethidine microfluorography; cognition was tested with novel object recognition and Barnes maze; data were analyzed by Student’s t test or ANOVA with Bonferroni/Tukey tests, with P < 0.05 considered significant.
Limitations
- The paper states that the molecular interactions of PVMs with cells of the neurovascular unit and their role in BBB alteration remain to be defined, and that the mechanisms of ANGII-induced BBB permeability increase remain to be established.
- The paper states that the rescue by Nox2 deletion in PVMs was not complete, possibly implicating ROS sources other than NOX2 or the 20%–30% of PVMs not replaced by transplant.
- The paper states that bone marrow chimera experiments could not be performed in BPH/2J mice because of their complex genetic background, and that cognitive function was not assessed in ANGII-treated mice because longer ANGII exposure is needed and is not compatible with the time course of PVM depletion by clodronate.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
0 of 39 cited sources checked · 0 supported · 0 flagged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast to FITC-dextran and sodium fluorescein, the BBB permeability to Evans blue, which binds to serum albumin (MW ~69 kDa), was not altered by chronic ANGII administration (Supplemental Figure 2E), indicating a previously unappreciated size restriction in the BBB dysfunction.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > jci.org Volume 126 Number 12 December 2016
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The effect of ANGII on the BBB could not be attributed solely to the elevation in BP, since 2 weeks of phenylephrine infusion increased BP comparably to ANGII, but did not alter BBB permeability to FITC-dextran (Supplemental Figure 2, G and H).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > jci.org Volume 126 Number 12 December 2016
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Infusion of low concentrations of ANGII (600 ng/kg/min) induced a delayed increase in BP that was observed at day 7 and leveled off by day 14 (Figure 2A).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Slow pressor ANGII disrupts the BBB, leading to ANGII entry into the perivascular space.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“First, we showed that in the slow pressor model of hypertension ANGII crosses the BBB and reaches PVMs in the perivascular space, demonstrating that these cells have access to circulating ANGII.”
- Also stated in: § Discussion · boosted
“Experiments with biotinylated ANGII demonstrated more directly that ANGII reaches the perivascular space and enters in contact with PVMs.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Discussion · boosted
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In both At1r -/-→WT and Nox2 -/-→WT chimeras, the increase in ROS induced by ANGII was attenuated (Figure 7, C and D)”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Deletion of At1r or Nox2 in PVMs attenuates ANGII-induced vascular oxidative stress.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that BPH/2J mice exhibit cerebrovascular impairment as well as cognitive dysfunction.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The cerebrovascular and cognitive deficits in BPH/2J mice are representative of hypertension-induced dysfunction rather than unrelated genetic traits.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Next, we demonstrated that PVM depletion using CLOD does not alter baseline cerebrovascular responses, but rescues the neurovascular dysfunction induced by slow pressor ANGII administration, or observed in a genetic model of lifelong hypertension.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Clodronate liposome treatment selectively depletes perivascular macrophages without affecting other cell types or processes that could rescue neurovascular or cognitive function.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Next, we demonstrated that PVM depletion using CLOD does not alter baseline cerebrovascular responses, but rescues the neurovascular dysfunction induced by slow pressor ANGII administration, or observed in a genetic model of lifelong hypertension.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Clodronate liposome treatment selectively depletes perivascular macrophages without affecting other cell types or processes that could rescue neurovascular or cognitive function.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that BPH/2J mice exhibit cerebrovascular impairment as well as cognitive dysfunction.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The cerebrovascular and cognitive deficits in BPH/2J mice are representative of hypertension-induced dysfunction rather than unrelated genetic traits.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The effect was specific for the neurovascular dysfunction of ANGII, since At1r deletion in PVMs did not rescue the dysfunction induced by the amyloid-β peptide.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 49
- The quote only partly states this claim. 3
- Probably not a substantial claim. 25
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As shown in Figure 2, D-F, nearly 60% of the PVMs were closely associated with biotinylated ANGII in mice treated with ANGII for 14 days (Figure 2, D-F).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > jci.org Volume 126 Number 12 December 2016
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one. The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that chronic ANGII infusion increased the permeability of the BBB to both markers at 14 days, whereas acute administration of ANGII (250 ng/kg/min) produced a comparable elevation in mean BP, but failed to do so (Figure 2C and Supplemental Figure 2E).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Slow pressor ANGII disrupts the BBB, leading to ANGII entry into the perivascular space.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, BPH/2J mice spent equal time exploring the novel and the familiar object, reflecting a deficit in recognition memory (Figure 9A).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Deletion of At1r or Nox2 in PVMs attenuates ANGII-induced vascular oxidative stress.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“BPH/2J mice exhibited elevated BP at 4 weeks of age (Supplemental Figure 5A), compared with normotensive controls, and the BP elevation remained stable until the mice were studied at 4-6 months of age.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Deletion of At1r or Nox2 in PVMs attenuates ANGII-induced vascular oxidative stress.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The CBF dysfunction was counteracted by neocortical application of the AT1R antagonist losartan or the ROS scavenger MnTBAP (Figure 8B)”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Deletion of At1r or Nox2 in PVMs attenuates ANGII-induced vascular oxidative stress.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At this time, levels of ANGII were elevated in plasma but not brain (Supplemental Figure 5, B and C).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Deletion of At1r or Nox2 in PVMs attenuates ANGII-induced vascular oxidative stress.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“CLOD treatment did not affect the performance of the normotensive controls and the total exploration time in both groups, but greatly ameliorated the memory deficit in BPH/2J mice (Figure 9A).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Deletion of At1r or Nox2 in PVMs attenuates ANGII-induced vascular oxidative stress.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, in At1r -/-→WT chimeras CBF responses to neural activation and ACh were markedly improved (Figure 5D).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > PVM depletion by clodronate restores neurovascular function in ANGII slow pressor hypertension.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, in ANGII-treated mice CLOD counteracted the attenuation of the vascular responses (Figure 3D), implicating PVMs in the mechanisms of the dysfunction.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > jci.org Volume 126 Number 12 December 2016
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Brain PVMs were identified as myeloid cells closely associated with the abluminal side of cerebral blood vessels and (a) expressing the mannose receptor CD206 (Figure 1 1D); (c) expressing low levels of IBA1, compared with microglial cells (Figure 1C); and (d) endowed of phagocytic activity assessed by injection of dextran into the lateral ventricles (Figure 1, B-D, and ref. 26).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Characterization of PVMs.
What the sources say
- Not checked yetcites [26] source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At this time, ANGII concentration was increased in plasma (Figure 2B), but not in brain (Supplemental Figure 2, A-C).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Slow pressor ANGII disrupts the BBB, leading to ANGII entry into the perivascular space.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ANGII hypertension or chronic elevation of BP in BPH/2J mice does not increase the number of PVMs or alter their homing from the circulation to the perivascular space.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“CLOD administration (i.c.v.) in BPH/2J mice depleted PVMs in both cortex and hippocampus (Supplemental Figure 5, D and E), and rescued the response to both whisker stimulation and ACh (Figure 8D).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Deletion of At1r or Nox2 in PVMs attenuates ANGII-induced vascular oxidative stress.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Using BM chimeras we provided evidence that replacement of WT PVMs with PVMs lacking AT1Rs or NOX2 abrogates the vascular oxidative stress induced by ANGII and counteracts the associated neurovascular dysfunction.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: In bone marrow chimeras, the donor genotype in perivascular macrophages is responsible for the observed effects, rather than other donor-derived immune cells or indirect effects.
In the paper
“BBB permeability tended to increase before the onset of hypertension, like the cerebrovascular dysfunction, which is first observed 7 days after ANGII administration (54).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Discussion
What the sources say
- Not checked yetcites [54] source
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Using BM chimeras we provided evidence that replacement of WT PVMs with PVMs lacking AT1Rs or NOX2 abrogates the vascular oxidative stress induced by ANGII and counteracts the associated neurovascular dysfunction.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: In bone marrow chimeras, the donor genotype in perivascular macrophages is responsible for the observed effects, rather than other donor-derived immune cells or indirect effects.
In the paper
“PVMs were found most abundantly in association with pial and parenchymal vessels larger than 20 μm in diameter, particularly pial arterioles, a key site for flow regulation (7), the length of which was covered 70%-80% by PVMs (Supplemental Figure 1, A-E; supplemental material available online with this article; doi:10.1172/JCI86950DS1).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Characterization of PVMs.
What the sources say
- Not checked yetcites [7] source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The increase in CBF induced by functional hyperemia or ACh was attenuated, whereas the CBF response to adenosine was normal (Figure 8B and Supplemental Table 1), attesting to the integrity of the vasorelaxing function of the smooth muscle.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Deletion of At1r or Nox2 in PVMs attenuates ANGII-induced vascular oxidative stress.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that At1r -/-→WT chimeras were protected from the cerebrovascular dysfunction induced by neocortical application of ANGII, but not of amyloid-β (Figure 6, A and B)”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > PVM depletion by clodronate restores neurovascular function in ANGII slow pressor hypertension.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“weakly positive for the microglia marker IBA1 (C)”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Flow cytometry.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“expressing the endothelial lymphatic vessel marker LYVE1 (D)”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Flow cytometry.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“(B) Antagonism of AT1Rs with losartan or ROS scavenging with MnTBAP counteracts the neurovascular dysfunction in BPH/2J mice.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Flow cytometry.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“(C) Slow pressor hypertension but not acute i.v.ANGII administration increases BBB permeability to FITC-dextran (MW 3 kDa).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Flow cytometry.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“(C) CLOD tends to reduce the distance traveled in BPH/2J mice, but the effect does not reach statistical significance.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Flow cytometry.
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Administration of low doses of ANGII for 2 weeks, which results in a slow-developing rise in BP (“slow pressor” hypertension) (14), induces profound alterations in neurovascular coupling and endothelium-dependent vasodilation (10,15).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Introduction
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The cerebrovascular dysfunction is mediated by activation of ANGII type 1 receptors (AT1Rs) and vascular oxidative stress produced by a NOX2-containing NADPH oxidase (10,15).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Introduction
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Residing in the intracerebral perivascular space, delimited by the glia limitans and the vascular basement membrane (Virchow-Robin space), PVMs are closely apposed to the outer vessel wall and originate from hematopoietic precursors (18,20,21).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Slow pressor ANGII disrupts the BBB, leading to ANGII entry into the perivascular space.
What the sources say
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“As macrophages, PVMs express AT1Rs and have the potential to produce large amounts of ROS through NOX2 (23,24).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Slow pressor ANGII disrupts the BBB, leading to ANGII entry into the perivascular space.
What the sources say
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“This test is similar to the water maze navigation task in that it examines the ability of the mouse to learn and remember the location of a target zone (spatial learning and memory) (42).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Deletion of At1r or Nox2 in PVMs attenuates ANGII-induced vascular oxidative stress.
What the sources say
- Not checked yetcites [42] source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Subsequent studies with more moderate and long-lasting increases in BP or in models of chronic hypertension demonstrated in some cases regional ANGII-dependent increases in BBB permeability (e.g., ref. 55), but it remained unclear whether ANGII itself was able to cross the BBB in slow pressor ANGII hypertension.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Discussion
What the sources say
- Not checked yetcites [55] source
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“In addition, innate immune cells, particularly macrophages, have been implicated in vascular remodeling and atherosclerosis through the production of ROS and cytokines (19).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Discussion
What the sources say
- Not checked yetcites [19] source
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“CLOD depleted PVMs by 60%-65% in mice receiving vehicle or ANGII (Figure 3B), but did not alter the increase in BP (Figure 3C and Supplemental Figure 3E).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > jci.org Volume 126 Number 12 December 2016
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Pioneering studies in lymphocyte-deficient mice (Rag1 -/-mice) established that T lymphocytes are required for the BP elevations in several hypertension models (61).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Discussion
What the sources say
- Not checked yetcites [61] source
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Although plasma levels of ANGII are not consistently elevated in essential hypertension (13), activation of tissue-specific renin-angiotensin systems, including in brain and blood vessels, is thought to play a role (62).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Experimental protocol for CBF experiments.
What the sources say
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No effect of At1r deletion or ANGII administration on PVM numbers was found (Supplemental Figure 4E).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > PVM depletion by clodronate restores neurovascular function in ANGII slow pressor hypertension.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This effect was mediated by an increase in blood-brain barrier permeability that allowed angiotensin II to enter the perivascular space and activate angiotensin type 1 receptors in PVMs, leading to production of ROS through the superoxide-producing enzyme NOX2.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Introduction
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our data implicate brain PVMs in the cognitive deficits induced by hypertension, and identify resident brain PVMs as a novel constituent of the NVU highly relevant to brain pathophysiology.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, PVMs emerge as a novel source of vascular oxidative stress in the cerebral microcirculation with a profound impact on neurovascular regulation and cognitive function.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“To examine the role of PVMs in the cognitive deficits in BPH/2J mice, we first used the novel object recognition task, a test of recognition memory that relies on the propensity of mice to explore novel objects more than familiar ones (41).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Deletion of At1r or Nox2 in PVMs attenuates ANGII-induced vascular oxidative stress.
What the sources say
- Not checked yetcites [41] source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“BPH/2J mice are a model of lifelong hypertension on a genetic basis and manifest some of the cardinal features of essential hypertension, i.e., neurohumoral dysfunction, sympathetic activation, cardiac hypertrophy, and kidney atrophy (58,59).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Although early studies described BBB opening by sudden increases in BP induced by high concentrations of ANGII or other pressor agents, these investigations used massive increases in BP that caused acute vascular damage and total vasoparalysis (57).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Discussion
What the sources say
- Not checked yetcites [57] Mayhan, 1986, Disruption of the blood-brain barrier in cerebrum and brain stem during acute hypertension, Am J Physiol
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“However, the Barnes maze has the advantage of avoiding the strong aversive stimulus of swimming that may affect performance (43).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Deletion of At1r or Nox2 in PVMs attenuates ANGII-induced vascular oxidative stress.
What the sources say
- Not checked yetcites [43] source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In this study, we elected to use middle-aged BPH/2J mice, a model of spontaneous lifelong hypertension resulting in well-documented and reproducible cognitive deficits (38).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Deletion of At1r or Nox2 in PVMs attenuates ANGII-induced vascular oxidative stress.
What the sources say
- Not checked yetcites [38] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“However, the rescue of the dysfunction was not complete, possibly implicating ROS sources other than NOX2 (33).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > PVM AT1Rs participate in the harmful cerebrovascular effects of ANGII.
What the sources say
- Not checked yetcites [33] source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“indicating that the neurovascular alterations are mediated by AT1Rs and ROS.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Deletion of At1r or Nox2 in PVMs attenuates ANGII-induced vascular oxidative stress.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The CBF dysfunction was counteracted by neocortical superfusion with the AT1R antagonist losartan or the ROS scavenger MnTBAP, implicating AT1Rs and ROS in its mechanisms.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“The effect is mediated by infiltration of the vascular wall by T lymphocytes and macrophages leading to production of deleterious cytokines, such as IL-17 and TNF-α, which, in turn, contribute to the increased vascular resistance driving the hypertension, as well as end-organ damage (61).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Discussion
What the sources say
- Not checked yetcites [61] source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Increasing evidence indicates that adaptive immunity and innate immunity play a key role in the pathogenesis of hypertension and in the associated end-organ damage (60).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Discussion
What the sources say
- Not checked yetcites [60] source
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“WT mice engrafted with WT BM (WT→WT) exhibited normal cerebrovascular reactivity and attenuation by ANGII (Figure 5D), indicating that the irradiation and BM transplantation did not alter basic CBF responses and their susceptibility to ANGII.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > PVM depletion by clodronate restores neurovascular function in ANGII slow pressor hypertension.
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, PVMs become the target of circulating ANGII, leading to engagement of AT1Rs, NOX2-dependent ROS formation, and neurovascular and cognitive dysfunction.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: In bone marrow chimeras, the donor genotype in perivascular macrophages is responsible for the observed effects, rather than other donor-derived immune cells or indirect effects.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Similarly, in vehicle-treated mice CLOD did not affect the CBF increases evoked by whisker stimulation, ACh, or adenosine (Figure 3D and Supplemental Table 1).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > jci.org Volume 126 Number 12 December 2016
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Neurovascular coupling and BBB are altered in essential hypertension (63), and observational studies indicate that ANGII antagonists can protect the brain from hypertension-induced cognitive dysfunction (64).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Experimental protocol for CBF experiments.
What the sources say
- Not checked yetcites [64] source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The findings unveil a previously unappreciated role of PVMs in the full expression of the neurovascular and neurocognitive dysfunction of hypertension, and identify PVMs as a new cellular component of the NVU of critical importance for neurovascular diseases associated with vascular oxidative stress.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Experimental protocol for CBF experiments.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The specificity of the immunofluorescence was verified by omission of the FITC-conjugated antibody or by use of the anti-biotin antibody in the absence of biotinylated ANGII.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > jci.org Volume 126 Number 12 December 2016
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
In the paper
“However, evidence from randomized clinical trials that treatment of hypertension reduces dementia risk and that there is a class-specific effect of drugs targeting ANGII and its receptors is lacking (3).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Experimental protocol for CBF experiments.
What the sources say
- Not checked yetcites [3] source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“circulating ANGII reaches the perivascular space through a breach of the BBB and acts on ANGII type 1 receptors (AT1R) on PVMs, resulting in the activation of NOX2 and ROS production.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Flow cytometry.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Bone marrow-derived cells that replace CD206+ cells in the brain after transplantation are perivascular macrophages and not other cell types.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Exploratory behavior was later assessed manually by an experimenter blinded to the treatment group.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > jci.org Volume 126 Number 12 December 2016
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
In the paper
“Neurovascular coupling and BBB are altered in essential hypertension (63), and observational studies indicate that ANGII antagonists can protect the brain from hypertension-induced cognitive dysfunction (64).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Experimental protocol for CBF experiments.
What the sources say
- Not checked yetcites [63] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Studies were conducted, according to ARRIVE guidelines (https://www.nc3rs.org.uk/arrive-guidelines), in male C57BL/6 mice (age 3-5 months, weight 25-30 g; JAX, The Jackson Laboratory), in male BPH/2J mice (age 5 months, weight 20-25 g; JAX stock 003005), and in their respective controls, male BPN/3J mice (age 5 months, weight 25-30 g; JAX stock 003004).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > General surgical procedures.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No animals were excluded, animals were randomly assigned to treatment and control groups, and analysis was performed in a blinded fashion.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > jci.org Volume 126 Number 12 December 2016
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“CD206 + cells were counted by an investigator blinded to the treatment on 10 randomly selected fields (×20 objective) within the somatosensory cortex and the hippocampus.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > jci.org Volume 126 Number 12 December 2016
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Reconstitution of BM cells was verified 5 weeks after irradiation by testing of the percentage of positive At1r or Nox2 genomic DNA in isolated blood leukocytes (65).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > General surgical procedures.
What the sources say
- Not checked yetcites [65] source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“HE is a cell-permeant dye that is oxidized by superoxide (68).”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Flow cytometry.
What the sources say
- Not checked yetcites [68] source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Sample size was determined according to power analysis.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > jci.org Volume 126 Number 12 December 2016
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No animals were excluded, animals were randomly assigned to treatment and control groups, and analysis was performed in a blinded fashion.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > jci.org Volume 126 Number 12 December 2016
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“CD206 + cells associated with biotinylated ANGII were counted by an investigator blinded to the treatment on randomly selected fields (×40 objective) within the somatosensory cortex.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > jci.org Volume 126 Number 12 December 2016
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Appropriate isotype control antibodies, “fluorescence minus one” staining, and staining of negative populations were used to establish sorting parameters.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > Flow cytometry.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No animals were excluded, animals were randomly assigned to treatment and control groups, and analysis was performed in a blinded fashion.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > jci.org Volume 126 Number 12 December 2016
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In chimeric mice, CBF experiments were performed 14 weeks after the BM transplant when most of the host PVMs have been replaced by donor macrophages.”
§ Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension > jci.org Volume 126 Number 12 December 2016
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
The paper relies on this without support.
The factors responsible for the functional alterations of the neurovascular unit in hypertension are poorly understood.
“The factors responsible for these functional alterations of the NVU are poorly understood, and their exploration is essential to develop preventative or therapeutic approaches to mitigate the impact of hypertension on brain health.”
The paper relies on this without support.
The vascular cell type that produces ROS and initiates the cerebrovascular dysfunction in ANGII hypertension remains unknown.
“However, the vascular cell type(s) that produces reactive oxygen species (ROS) and initiates the dysfunction remains to be elucidated.”
The paper relies on this without support.
It is unclear whether neurovascular dysfunction is required for the development of cognitive deficits.
“Furthermore, it is unclear whether the neurovascular dysfunction is required for the development of cognitive deficits.”
The paper relies on this without support.
BPH/2J mice are a more representative model of chronic hypertension in humans than the slow-pressor ANGII model.
“To overcome these limitations, we also examined the role of PVMs in a model of spontaneous lifelong hypertension more representative of chronic hypertension in humans.”
The paper relies on this without support.
Clodronate liposome treatment selectively depletes perivascular macrophages without affecting other cell types or processes that could rescue neurovascular or cognitive function.
“To deplete cerebral CD206 + macrophages, clodronate-or PBS-loaded liposomes were prepared as previously described (27).”
The paper relies on this without support.
In bone marrow chimeras, the donor genotype in perivascular macrophages is responsible for the observed effects, rather than other donor-derived immune cells or indirect effects.
“Using BM chimeras we provided evidence that replacement of WT PVMs with PVMs lacking AT1Rs or NOX2 abrogates the vascular oxidative stress induced by ANGII and counteracts the associated neurovascular dysfunction.”
The paper relies on this without support.
The cerebrovascular and cognitive deficits in BPH/2J mice are representative of hypertension-induced dysfunction rather than unrelated genetic traits.
“BPH/2J mice are a model of lifelong hypertension on a genetic basis and manifest some of the cardinal features of essential hypertension, i.e., neurohumoral dysfunction, sympathetic activation, cardiac hypertrophy, and kidney atrophy (58,59).”
The paper relies on this without support.
CLOD selectively depletes perivascular macrophages without affecting other brain cells.
“(A and B) Intracerebroventricular CLOD administration induces depletion of cells expressing the PVM marker CD206 in the somatosensory cortex assessed by histology.”
The paper relies on this without support.
Bone marrow-derived cells that replace CD206+ cells in the brain after transplantation are perivascular macrophages and not other cell types.
“(B) By 14 weeks after the transplant, approximately 80% of CD206 + cells in the somatosensory cortex are replaced by GFP + bone marrow cells.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“LD accumulation in macrophages can elevate their ROS production (9, 11), promoting neurovascular dysfunction (67).”
From Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model (2025) · cites this paper as [67]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Being directly exposed to peripheral stimuli, they can respond to inflammatory and chemical cues, including signals from microbiota [369] and mechanical cues [370].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [370]
Experimental — accuracy not yet measuredIn the citing paper
“Hypertension is a leading risk factor for depression incidence in obesity and causes neurovascular changes that involve the actions of perivascular macrophages to stimulate oxidative stress and inflammation that lead to cognitive dysfunction [166].”
From The menace of obesity to depression and anxiety prevalence (2022) · cites this paper as [166]
Citations
Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860
Mutation of the mouse klotho gene leads to a syndrome resembling ageing
Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997) · Nature · doi:10.1038/36285 · Cited by 3,837
Gorelick, P. B., Scuteri, A., Black, S. E., DeCarli, C., Greenberg, S. M., Iadecola, C., Launer, L. J., Laurent, S., Lopez, O. L., Nyenhuis, D., et al. (2011) · Stroke · doi:10.1161/str.0b013e3182299496 · Cited by 3,811 · cited 2×
“However, evidence from randomized clinical trials that treatment of hypertension reduces dementia risk and that there is a class-specific effect of drugs targeting ANGII and its receptors is lacking (3).”
Self-citationCell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq
Zeisel, A., Muñoz-Manchado, A. B., Codeluppi, S., Lönnerberg, P., La Manno, G., Juréus, A., Marques, S., Munguba, H., He, L., Betsholtz, C., et al. (2015) · Science · doi:10.1126/science.aaa1934 · Cited by 3,124
Macrophages in atherosclerosis: a dynamic balance
Moore, K. J., Sheedy, F. J., & Fisher, E. A. (2013) · Nature reviews. Immunology · doi:10.1038/nri3520 · Cited by 2,559
Glial and neuronal control of brain blood flow
Attwell, D., Buchan, A. M., Charpak, S., Lauritzen, M., MacVicar, B. A., & Newman, E. A. (2010) · Nature · doi:10.1038/nature09613 · Cited by 2,511
Identification of splenic reservoir monocytes and their deployment to inflammatory sites
Swirski, F. K., Nahrendorf, M., Etzrodt, M., Wildgruber, M., Cortez-Retamozo, V., Panizzi, P., Figueiredo, J.-L., Kohler, R. H., Chudnovskiy, A., Waterman, P., et al. (2009) · Science · doi:10.1126/science.1175202 · Cited by 2,221
Neurovascular regulation in the normal brain and in Alzheimer's disease
Iadecola, C. (2004) · Nature Reviews Neuroscience · doi:10.1038/nrn1387 · Cited by 2,213
Self-citationMemory deficits associated with senescence: A neurophysiological and behavioral study in the rat.
Barnes, C. A. (1979) · Journal of Comparative and Physiological Psychology · doi:10.1037/h0077579 · Cited by 2,088
The Pathobiology of Vascular Dementia
Iadecola, C. (2013) · Neuron · doi:10.1016/j.neuron.2013.10.008 · Cited by 1,857
Self-citation
Flagged first, then by citations
2 of the 71 references couldn’t be matched to a known paper.
Research works printed but not linked: 2
- 10.1006/exnr.2000.7618 · DOI · Paper page
- 10.1152/ajpheart.00679.2010 · DOI · Paper page
Cited by
Sorted by citations
The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease
Iadecola, C. (2017) · Neuron · doi:10.1016/j.neuron.2017.07.030 · Cited by 2,480
Self-citationAngiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology
Forrester, S. J., Booz, G. W., Sigmund, C. D., Coffman, T. M., Kawai, T., Rizzo, V., Scalia, R. G., & Eguchi, S. (2018) · Physiological Reviews · doi:10.1152/physrev.00038.2017 · Cited by 1,135
Vascular Cognitive Impairment and Dementia
Iadecola, C., Duering, M., Hachinski, V., Joutel, A., Pendlebury, S. T., Schneider, J. A., & Dichgans, M. (2019) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2019.04.034 · Cited by 865
Self-citationvan der Flier, W. M., Skoog, I. G., Schneider, J. A., Pantoni, L., Mok, V., Chen, C., & Scheltens, P. (2018) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2018.3 · Cited by 606
Hypertension-induced cognitive impairment: From pathophysiology to public health
Ungvari, Z., Toth, P., Tarantini, S., Prodan, C. I., Sorond, F., Merkely, B., & Csiszar, A. (2021) · Nature Reviews Nephrology · doi:10.1038/s41581-021-00430-6 · Cited by 544
Neurovascular and Cognitive Dysfunction in Hypertension
Iadecola, C., & Gottesman, R. F. (2019) · Circulation Research · doi:10.1161/circresaha.118.313260 · Cited by 530
“Because in BPH mice and in the slow-pressor model Ang II is elevated in the circulation but not in brain, circulating Ang II was found to cross the BBB and gain access to PVM on the abluminal side of the vessels (Figure 3).(74) Although PVMs are unlikely to be the sole source of vascular oxidative stress, the observat…”
BackgroundInfluentialSelf-citationIntegrated single cell analysis of blood and cerebrospinal fluid leukocytes in multiple sclerosis
Schafflick, D., Xu, C. A., Hartlehnert, M., Cole, M. B., Schulte‐Mecklenbeck, A., Lautwein, T., Wolbert, J., Heming, M., Meuth, S. G., Kuhlmann, T., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-14118-w · Cited by 457
The menace of obesity to depression and anxiety prevalence
Fulton, S., Décarie-Spain, L., Fioramonti, X., Guiard, B., & Nakajima, S. (2022) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2021.10.005 · Cited by 441
“stress and inflammation that lead to cognitive dysfunction [166].”
BackgroundMacrophages at CNS interfaces: Ontogeny and function in health and disease
Kierdorf, K., Masuda, T., Jordão, M. J. C., & Prinz, M. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-019-0201-x · Cited by 416
Duncombe, J., Kitamura, A., Hase, Y., Ihara, M., Kalaria, R. N., & Horsburgh, K. J. (2017) · Clinical Science · doi:10.1042/cs20160727 · Cited by 416
Alzheimer’s Disease and Vascular Aging
Cortes-Canteli, M., & Iadecola, C. (2020) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2019.10.062 · Cited by 400
“Recent evidence implicating perivascular macrophages in the vascular oxidative stress induced by hypertension support this hypothesis (56) because Ab is cleared in part through the perivascular space, alterations of which are linked to cognitive impairment (1,23).”
BackgroundSelf-citationOntogeny and homeostasis of CNS myeloid cells
Prinz, M., Erny, D., & Hagemeyer, N. (2017) · Nature Immunology · doi:10.1038/ni.3703 · Cited by 413
Transforming the understanding of brain immunity
Castellani, G., Croese, T., Peralta Ramos, J. M., & Schwartz, M. (2023) · Science · doi:10.1126/science.abo7649 · Cited by 386
“Additional studies have identified specialized immunological compartments within the brain, including the meninges (36–39), the choroid plexus (40–42), and the perivascular spaces (43, 44), forming niches from which immune cells could affect the CNS without interfering with its delicate neuronal network.”
BackgroundLim, H. Y., Lim, S. Y., Tan, C. K., Thiam, C. H., Goh, C. C., Carbajo, D., Chew, S. H. S., See, P., Chakarov, S., Wang, X. N., et al. (2018) · Immunity · doi:10.1016/j.immuni.2018.06.008 · Cited by 384
Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response
Faraco, G., Brea, D., Garcia-Bonilla, L., Wang, G., Racchumi, G., Chang, H., Buendia, I., Santisteban, M. M., Segarra, S. G., Koizumi, K., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-017-0059-z · Cited by 343
Self-citationUnderstanding the role of the perivascular space in cerebral small vessel disease
Brown, R., Benveniste, H., Black, S. E., Charpak, S., Dichgans, M., Joutel, A., Nedergaard, M., Smith, K. J., Zloković, B. V., & Wardlaw, J. M. (2018) · Cardiovascular Research · doi:10.1093/cvr/cvy113 · Cited by 346
Animal Models of Hypertension: A Scientific Statement From the American Heart Association
Lerman, L. O., Kurtz, T. W., Touyz, R. M., Ellison, D. H., Chade, A., Crowley, S. D., Mattson, D. L., Mullins, J. J., Osborn, J. L., Eirin, A., et al. (2019) · Hypertension · doi:10.1161/hyp.0000000000000090 · Cited by 351
Self-citationInflammation in ALS/FTD pathogenesis
McCauley, M. E., & Baloh, R. H. (2019) · Acta Neuropathologica · doi:10.1007/s00401-018-1933-9 · Cited by 341
“These cells produce copious amounts of ROS, alter the neurovasculature of the CNS, recruit circulating immune cells, and incite systemic inflammation [40, 41, 66].”
BackgroundParenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid
Drieu, A., Du, S., Storck, S. E., Rustenhoven, J., Papadopoulos, Z., Dykstra, T., Zhong, F., Kim, K., Blackburn, S., Mamuladze, T., et al. (2022) · Nature · doi:10.1038/s41586-022-05397-3 · Cited by 325
Preventing dementia by preventing stroke: The Berlin Manifesto
Hachinski, V., Einhäupl, K. M., Ganten, D., Alladi, S., Brayne, C., Stephan, B. C. M., Sweeney, M. D., Zloković, B. V., Iturria‐Medina, Y., Iadecola, C., et al. (2019) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2019.06.001 · Cited by 324
“More recently, it was found that perivascular macrophages are the major source of cerebrovascular oxidative stress in mouse models of life-long hypertension [73].”
BackgroundSelf-citationNeuroprotective effect of SGLT2 inhibitors.
Pawlos, A., Broncel, M., Woźniak, E., & Gorzelak-Pabiś, P. (2021) · Molecules · doi:10.3390/molecules26237213 · Cited by 304
“Macrophages take part in cognitive impairment as perivascular macrophages (PVM) are the source of vascular oxidative stress by producing a large amount of free radicals near the neurovascular unit [90].”
BackgroundFrąk, W., Wojtasińska, A., Lisińska, W., Młynarska, E., Franczyk, B., & Rysz, J. (2022) · Biomedicines · doi:10.3390/biomedicines10081938 · Cited by 284
“In one study, perivascular macrophages were associated with the neurovascular and cognitive dysfunction induced by AH [84].”
BackgroundSpecification of CNS macrophage subsets occurs postnatally in defined niches
Masuda, T., Amann, L., Monaco, G., Sankowski, R., Staszewski, O., Krueger, M., Del Gaudio, F., He, L., Paterson, N., Nent, E., et al. (2022) · Nature · doi:10.1038/s41586-022-04596-2 · Cited by 294
Hypertension, Neurovascular Dysfunction, and Cognitive Impairment
Santisteban, M. M., Iadecola, C., & Carnevale, D. (2022) · Hypertension · doi:10.1161/hypertensionaha.122.18085 · Cited by 317
Self-citationResident and Monocyte-Derived Macrophages in Cardiovascular Disease
Honold, L., & Nahrendorf, M. (2018) · Circulation Research · doi:10.1161/circresaha.117.311071 · Cited by 283
“tricles, an approach that has been applied to specifically eliminate perivascular macrophages in the brain.(169) The technique’s”
Microglia modulate blood flow, neurovascular coupling, and hypoperfusion via purinergic actions
Császár, E., Lénárt, N., Cserép, C., Környei, Z., Fekete, R., Pósfai, B., Balázsfi, D., Hangya, B., Schwarcz, A. D., Szabadits, E., et al. (2022) · The Journal of Experimental Medicine · doi:10.1084/jem.20211071 · Cited by 274
“tricle (ICV) as described earlier (Faraco et al., 2016).”
Brain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer Aβ Peptides
Park, L., Uekawa, K., Garcia-Bonilla, L., Koizumi, K., Murphy, M., Pistik, R., Younkin, L., Younkin, S., Zhou, P., Carlson, G., et al. (2017) · Circulation Research · doi:10.1161/circresaha.117.311054 · Cited by 259
Self-citationPerivascular macrophages in health and disease
Lapenna, A., Palma, M. D., & Lewis, C. E. (2018) · Nature reviews. Immunology · doi:10.1038/s41577-018-0056-9 · Cited by 268
Hainsworth, A. H., Markus, H. S., & Schneider, J. A. (2023) · Hypertension · doi:10.1161/hypertensionaha.123.19943 · Cited by 286
“44,115 The dramatis personae of the neurovascular unit, including pericytes, myofibroblasts, and perivascular macrophages 116 are all likely participants.”
BackgroundBrain borders at the central stage of neuroimmunology
Rustenhoven, J., & Kipnis, J. (2022) · Nature · doi:10.1038/s41586-022-05474-7 · Cited by 253
Dietary salt promotes cognitive impairment through tau phosphorylation
Faraco, G., Hochrainer, K., Segarra, S. G., Schaeffer, S., Santisteban, M. M., Menon, A., Jiang, H., Holtzman, D. M., Anrather, J., & Iadecola, C. (2019) · Nature · doi:10.1038/s41586-019-1688-z · Cited by 236
Self-citationZloković, B. V., Gottesman, R. F., Bernstein, K. E., Seshadri, S. S., McKee, A. C., Snyder, H. M., Greenberg, S. M., Yaffe, K. S., Schaffer, C. B., Yuan, C., et al. (2020) · Alzheimer s & Dementia · doi:10.1002/alz.12157 · Cited by 252
Hemorrhagic Transformation in Ischemic Stroke and the Role of Inflammation
Spronk, E., Sykes, G. P., Falcione, S. R., Munsterman, D., Joy, T., Tatuene, J. K., & Jickling, G. C. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.661955 · Cited by 241
Inflammation and Stroke Risk: A New Target for Prevention
Kelly, P. J., Lemmens, R., & Tsivgoulis, G. K. (2021) · Stroke · doi:10.1161/strokeaha.121.034388 · Cited by 218
Yanagida, K., Liu, C. H., Faraco, G., Galvani, S., Smith, H. K., Burg, N. D., Anrather, J., Sánchez, T., Iadecola, C., & Hla, T. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1618659114 · Cited by 222
“Of note, chronic, but not acute, hypertension increases BBB leakage for small molecules, which causes cognitive impairment by enhancing exposure of angiotensin II to perivascular macrophage (30).”
BackgroundMethodInfluentialSelf-citationBrain perivascular macrophages: characterization and functional roles in health and disease
Faraco, G., Park, L., Anrather, J., & Iadecola, C. (2017) · Journal of Molecular Medicine · doi:10.1007/s00109-017-1573-x · Cited by 206
“BPH mice exhibited neurovascular dysfunction dependent on circulating AngII, AT1R, and vascular oxidative stress [19], which was counteracted by PVM depletion [19].”
BackgroundInfluentialSelf-citationGe, X., Tang, P., Rong, Y., Jiang, D., Lu, X., Ji, C., Wang, J., Huang, C., Duan, A., Liu, Y., et al. (2021) · Redox Biology · doi:10.1016/j.redox.2021.101932 · Cited by 197
Endothelium-Macrophage Crosstalk Mediates Blood-Brain Barrier Dysfunction in Hypertension
Santisteban, M. M., Ahn, S. J., Lane, D., Faraco, G., García‐Bonilla, L., Racchumi, G., Poon, C., Schaeffer, S. M., Segarra, S. G., Körbelin, J., et al. (2020) · Hypertension · doi:10.1161/hypertensionaha.120.15581 · Cited by 192
“Procedures for electron microscopy were identical to those previously described.(25,31) Cortical microvasculature was examined using a Technai transmission electron microscope outfitted with a CCD camera system (AMT Advantage).”
BackgroundMethodInfluentialSelf-citationCarvalho, C., & Moreira, P. I. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00806 · Cited by 184
Apoε4 disrupts neurovascular regulation and undermines white matter integrity and cognitive function
Koizumi, K., Hattori, Y., Ahn, S. J., Buendia, I., Ciacciarelli, A., Uekawa, K., Wang, G., Hiller, A., Zhao, L., Voss, H. U., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06301-2 · Cited by 179
Self-citationAndjelkovic, A. V., Situ, M., Citalán‐Madrid, A. F., Stamatovic, S. M., Xiang, J., & Keep, R. F. (2023) · Stroke · doi:10.1161/strokeaha.122.040578 · Cited by 190
Schonhoff, A. M., Figge, D. A., Williams, G. P., Jurkuvenaite, A., Gallups, N. J., Childers, G. M., Webster, J. M., Standaert, D. G., Goldman, J. E., & Harms, A. S. (2023) · Nature Communications · doi:10.1038/s41467-023-39060-w · Cited by 161
“barrier permeability, produce reactive oxygen species, and are highly phagocytic, indicating they may play a role in disease pathogenesis as effectors or regulators of immune responses [14-16].”
Multiomic spatial landscape of innate immune cells at human central nervous system borders
Sankowski, R., Süß, P., Benkendorff, A., Böttcher, C., Fernandez-Zapata, C., Chhatbar, C., Cahueau, J., Monaco, G., Gasull, A. D., Khavaran, A., et al. (2024) · Nature Medicine · doi:10.1038/s41591-023-02673-1 · Cited by 156
Cellular and Molecular Characterization of Microglia: A Unique Immune Cell Population
Sousa, C., Biber, K. P. H., & Michelucci, A. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00198 · Cited by 159
“Nevertheless, non-parenchymal macrophages are strategically located at the brain boundaries and represent distinct and specialized populations of macrophages serving as key mediators for brain homeostasis and immune responses (107, 124, 125).”
BackgroundInfluentialIadecola, C., Smith, E. E., Anrather, J., Gu, C., Mishra, A., Misra, S., Pérez‐Pinzón, M. A., Shih, A. Y., Sorond, F. A., van Veluw, S. J., et al. (2023) · Stroke · doi:10.1161/str.0000000000000431 · Cited by 161
Self-citationPedragosa, J., Salas-Perdomo, A., Gallizioli, M., Cugota, R., Miró‐Mur, F., Briansó, F., Justicia, C., Pérez-Asensio, F. J., Márquez‐Kisinousky, L., Urra, X., et al. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0581-6 · Cited by 147
Hypertension, Neurodegeneration, and Cognitive Decline
Pacholko, A. G., & Iadecola, C. (2024) · Hypertension · doi:10.1161/hypertensionaha.123.21356 · Cited by 170
“Hypertension and Cognitive Decline in BP provoked by an α -adrenergic agonist fail to induce neurovascular dyfunction, 82 suggesting that not all pressor agents will affect these regulatory mechanisms.”
BackgroundInfluentialSelf-citationBrain macrophage development, diversity and dysregulation in health and disease
Silvin, A., Qian, J., & Ginhoux, F. (2023) · Cellular & Molecular Immunology · doi:10.1038/s41423-023-01053-6 · Cited by 137
“They also contribute to hypertensive pathogenesis, and PVMs recognize angiotensin II and produce ROS through NOX2 activation [42, 43].”
BackgroundTh17 and Cognitive Impairment: Possible Mechanisms of Action
Cipollini, V., Anrather, J., Orzi, F., & Iadecola, C. (2019) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2019.00095 · Cited by 133
Self-citationA novel perivascular cell population in the zebrafish brain
Galanternik, M. V., Castranova, D., Gore, A. V., Blewett, N. H., Jung, H. M., Stratman, A. N., Kirby, M., Iben, J., Miller, M. F., Kawakami, K., et al. (2017) · eLife · doi:10.7554/elife.24369 · Cited by 124
“Several studies in mammals have suggested that PVMs and/or FGPs are bone marrow-derived cells (Audoy-Rémus et al., 2008; Faraco et al., 2016).”
BackgroundInfluentialCardiovascular comorbidities, inflammation, and cerebral small vessel disease
Evans, L., Taylor, J. L., Smith, C. J., Pritchard, H. A. T., Greenstein, A. S., & Allan, S. M. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvab284 · Cited by 127
“not only lowered ROS production but significantly ameliorated cognitive function in the BPH-2 mouse model of spontaneous hypertension.(121)”
BackgroundPark, L., Hochrainer, K., Hattori, Y., Ahn, S. J., Anfray, A., Wang, G., Uekawa, K., Seo, J., Palfini, V. L., Blanco, I., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-0686-7 · Cited by 123
“Methods for cognitive testing have been described in detail previously 41, 69 and are only summarized.”
Self-citationSalt, Hypertension, and Immunity
Rucker, A. J., Rudemiller, N. P., & Crowley, S. D. (2017) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021317-121134 · Cited by 123
Liu, X., Hao, J., Yao, E., Cao, J., Zheng, X., Yao, D., Zhang, C., Li, J., Pan, D., Luo, X., et al. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.07.022 · Cited by 121
The role of macrophages in hypertension and its complications
Rucker, A. J., & Crowley, S. D. (2017) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-017-1950-x · Cited by 118
“PVMs were critical in hypertensive neurovascular dysfunction [27, 37].”
BackgroundThe pathogenesis of cerebral small vessel disease and vascular cognitive impairment
Markus, H. S., & Joutel, A. (2025) · Physiological Reviews · doi:10.1152/physrev.00028.2024 · Cited by 140
Hypertension, dietary salt and cognitive impairment
Santisteban, M. M., & Iadecola, C. (2018) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x18803374 · Cited by 107
Self-citationPathophysiology of cerebral small vessel disease: a journey through recent discoveries
Dupré, N., Drieu, A., & Joutel, A. (2024) · Journal of Clinical Investigation · doi:10.1172/jci172841 · Cited by 126
“In AngII-induced chronic hypertension, activation of AT1 receptors in perivascular macrophages (PVMs, a population of resident macrophages in the PVS) is involved in NVC deficits and leads to the production of reactive oxygen species, which impair endothelium-dependent responses (106).”
BackgroundSingle-cell transcriptomics reveals functionally specialized vascular endothelium in brain
Jeong, H., Diéguez‐Hurtado, R., Arf, H., Song, J., Park, H., Kruse, K., Sorokin, L. M., & Adams, R. H. (2022) · eLife · doi:10.7554/elife.57520 · Cited by 110
Rajan, W. D., Wojtaś, B., Gielniewski, B., Miró‐Mur, F., Pedragosa, J., Zawadzka, M., Pilanc, P., Planas, A. M., & Kaminska, B. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104722 · Cited by 106
“, 2006), and contribute to neurovascular dysfunction in Alzheimer’s disease and hypertension (Faraco et al., 2016; Park et al., 2017).”
Rostral Ventrolateral Medulla and Hypertension
Guyenet, P. G., Stornetta, R. L., Holloway, B. B., Souza, G. M. P. R., & Abbott, S. B. G. (2018) · Hypertension · doi:10.1161/hypertensionaha.118.10921 · Cited by 97
Brain perivascular macrophages: Recent advances and implications in health and diseases
Yang, T., Guo, R., & Zhang, F. (2019) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13263 · Cited by 97
Brain perivascular macrophages: current understanding and future prospects
Wen, W., Cheng, J., & Tang, Y. (2023) · Brain · doi:10.1093/brain/awad304 · Cited by 107
“35,66 Pharmacological depletion of microglia and PVMs by CSF1R inhibitor (PLX5622) also prevented short-term memory impairment in Ang II-induced hypertensive mice.”
BackgroundNeuropathology of White Matter Lesions, Blood–Brain Barrier Dysfunction, and Dementia
Hainsworth, A. H., Minett, T., Andoh, J., Forster, G., Bhide, I., Barrick, T. R., Elderfield, K., Jeevahan, J., Markus, H. S., & Bridges, L. (2017) · Stroke · doi:10.1161/strokeaha.117.018101 · Cited by 95
“In the brains of these mice, efflux of water and small solutes (including MRI contrast agents, molecular weight<1000) was evident, whereas large plasma protein molecules were retained.(11,26,33) Extravasation of small solutes may be associated with WMH, whereas larger solutes (including proteins such as fibrinogen) ar…”
Macrophages under pressure: the role of macrophage polarization in hypertension
Harwani, S. C. (2017) · Translational research · doi:10.1016/j.trsl.2017.10.011 · Cited by 95
“Activation of PVM leads to induction of ROS and is implicated in damaging neurocognitive and vascular effects of hypertension (93).”
BackgroundLevit, A., Hachinski, V., & Whitehead, S. N. (2020) · GeroScience · doi:10.1007/s11357-020-00164-6 · Cited by 96
“Additionally, dysregulated inflammation induced by AD pathology can further disrupt the NVU, while failure of perivascular macrophages to clear Aβ can contribute to its accumulation in the brain (Hawkes et al. 2009; Erickson and Banks 2013; Faraco et al. 2016b).”
BackgroundSympathetic Activation in Hypertension: Importance of the Central Nervous System
Hirooka, Y. (2020) · American Journal of Hypertension · doi:10.1093/ajh/hpaa074 · Cited by 88
Presa, J., Saravia, F., Bagi, Z. A., & Filosa, J. A. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.584135 · Cited by 97
“The authors further demonstrated that in BPH/2J mice, PVM depletion improved cognitive impairments, providing an important link between hypertension, PVM/inflammation, and cognitive dysfunction (Faraco et al., 2016).”
BackgroundCerebral Small Vessel Disease: a Review of the Pathophysiological Mechanisms
Hannawi, Y. (2023) · Translational Stroke Research · doi:10.1007/s12975-023-01195-9 · Cited by 99
“The perivascular macrophages (PVMs) have gained recent attention as the main source of superoxide in the brain in hypertension [112].”
Santisteban, M. M., Schaeffer, S. M., Anfray, A., Faraco, G., Brea, D., Wang, G., Sobanko, M., Sciortino, R. K., Racchumi, G., Waisman, A., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01497-z · Cited by 93
“BAMs, including perivascular and leptomeningeal macrophages, express IL-17RA 35 and have been implicated in models of neurovascular and cognitive dysfunction 21,36 , raising the possibility that they may also play a role in DOCA-salt HTN.”
InfluentialSelf-citationMunro, D. A. D., Wineberg, Y., Tarnick, J., Vink, C. S., Li, Z., Pridans, C., Dzierzak, E. A., Tomer Kalisky, C., Hohenstein, P., & Davies, J. A. (2019) · eLife · doi:10.7554/elife.43271 · Cited by 82
“Within the cortical nephrogenic zone, F4/80 macrophages typically co-stained for the mannose receptor, CD206, a marker associated with perivascular/mature macrophage status (Figure 3i– j) (Faraco et al., 2016; Galea et al., 2005).”
BackgroundUekawa, K., Hattori, Y., Ahn, S. J., Seo, J., Casey, N., Anfray, A., Zhou, P., Luo, W., Anrather, J., Park, L., et al. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00660-1 · Cited by 80
“The time interval after BM transplanta - tion determines whether the myeloid cell engraftment is limited to perivascular space and leptomeninges or involves also parenchymal microglia [24, 25, 50–53].”
BackgroundMethodInfluentialSelf-citationStructural and Functional Remodeling of the Brain Vasculature Following Stroke
Andrade, M. F., Raman‐Nair, J., & Lacoste, B. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00948 · Cited by 82
“Additionally, PVMs were shown to promote BBB degradation through ROS production in a mouse model of hypertension, which could be reversed by depleting PVMs, effectively reducing oxidative stress, improving CBF dysfunction, restoring neurovascular coupling, and rescuing cognitive impairment (Faraco et al., 2016).”
BackgroundCognitive Impairment in Heart Failure: Landscape, Challenges, and Future Directions
Yang, M., Sun, D., Wang, Y., Yan, M., Zheng, J., & Ren, J. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.831734 · Cited by 83
“Upon Ang-II binds to angiotensin receptor 1 in the PVMs, the NADPH oxidase 2 is activated to promote ROS overproduction (66, 67).”
BackgroundDeciphering the heterogeneity of the Lyve1+ perivascular macrophages in the mouse brain
Siret, C., van Lessen, M., Bavais, J., Jeong, H., Samawar, S. K. R., Kapupara, K., Wang, S., Simic, M., de Fabritus, L., Tchoghandjian, A., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-35166-9 · Cited by 80
Smooth muscle cells of intracranial vessels: from development to disease
Frösén, J., & Joutel, A. (2018) · Cardiovascular Research · doi:10.1093/cvr/cvy002 · Cited by 78
Lin, Z., Altaf, N., Li, C., Chen, M., Pan, L., Wang, D., Xie, L., Zheng, Y., Fu, H., Han, Y., et al. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.05.023 · Cited by 73
Neuroimmune axis of cardiovascular control: mechanisms and therapeutic implications
Carnevale, D. (2022) · Nature Reviews Cardiology · doi:10.1038/s41569-022-00678-w · Cited by 77
CNS border-associated macrophages in the homeostatic and ischaemic brain
Gerganova, G., Riddell, A., & Miller, A. A. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108220 · Cited by 72
Emodin Rescued Hyperhomocysteinemia-Induced Dementia and Alzheimer’s Disease-Like Features in Rats
Zeng, P. H., Shi, Y., Wang, X., Li, L., Du, Y., Tang, N., Wang, Q., Fang, Y., Wang, J., Zhou, X., et al. (2018) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyy090 · Cited by 74
“Cerebral hypoperfusion is a risk factor for cognitive impairments (Park et al., 2014; Garcia-Bonilla et al., 2015; Faraco et al., 2016).”
BackgroundKoizumi, T., Kerkhofs, D., Mizuno, T., Steinbusch, H. W. M., & Foulquier, S. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01291 · Cited by 74
Kerkhofs, D., van Hagen, B. T. J., Milanova, I. V., Schell, K. J., van Essen, H., Wijnands, E., Goossens, P., Blankesteijn, W. M., Unger, T., Prickaerts, J., et al. (2020) · Theranostics · doi:10.7150/thno.44394 · Cited by 75
“observed in earlier work [41] we found however a 60% reduction of the CD206+ PVM numbers due to the PLX5622 treatment.”
BackgroundMethodInfluentialc-MAF–dependent perivascular macrophages regulate diet-induced metabolic syndrome
Silva, H. M., Kitoko, J. Z., Queiroz, C. P., Kroehling, L., Matheis, F., Yang, K. L., Reis, B. S., Ren‐Fielding, C. J., Littman, D. R., Bozza, M. T., et al. (2021) · Science Immunology · doi:10.1126/sciimmunol.abg7506 · Cited by 75
Border-associated macrophages as gatekeepers of brain homeostasis and immunity
Vara‐Pérez, M., & Movahedi, K. (2025) · Immunity · doi:10.1016/j.immuni.2025.04.005 · Cited by 84
Current views on meningeal lymphatics and immunity in aging and Alzheimer’s disease
Rego, S., Sánchez, G., & Mesquita, S. D. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00645-0 · Cited by 79
“In a mouse model of hypertension induced by angiotensin 2, BAMs have been shown to contribute to increased levels of reactive oxygen species at the blood-brain barrier (BBB), and mediate, at least in part, the neuroinflammatory response that culminates in increased arteriole and venule permeability and worsened cognit…”
BackgroundPeng, Q., Hu, Y., Huang, M., Wu, Y., Zhong, P., Dong, X., Wu, Q., Liu, B., Li, C., Xie, J., et al. (2020) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.61.8.42 · Cited by 69
CNS Border-Associated Macrophages: Ontogeny and Potential Implication in Disease
Dermitzakis, I., Theotokis, P., Evangelidis, P., Delilampou, E., Evangelidis, N., Chatzisavvidou, A., Avramidou, E., & Μanthou, M. E. (2023) · Current Issues in Molecular Biology · doi:10.3390/cimb45050272 · Cited by 74
“The pvM Φ manifested higher levels of CD45 and lower IBA1 in relation to microglia [8,83].”
BackgroundSwanson, M. E. V., Murray, H. C., Ryan, B., Faull, R. L. M., Dragunow, M., & Curtis, M. A. (2020) · Scientific Reports · doi:10.1038/s41598-020-68086-z · Cited by 65
Cognitive impairment in myocardial infarction and heart failure
Jinawong, K., Apaijai, N., Chattipakorn, N., & Chattipakorn, S. C. (2021) · Acta Physiologica · doi:10.1111/apha.13642 · Cited by 69
Csiszár, A., Ungvari, A., Patai, R., Gulej, R., Yabluchanskiy, A., Benyó, Z., Kovács, I., Sótonyi, P., Kirkpartrick, A. C., Prodan, C. I., et al. (2024) · GeroScience · doi:10.1007/s11357-024-01139-7 · Cited by 75
“It upregulates both NADPH oxidase and mitochondria-dependent ROS production, decreasing NO bioavailability, activating inflammatory processes, and causing structural damage to endothelial cells [298, 302–307].”
BackgroundReducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model
Wu, X., Miller, J. A., Lee, B. T. K., Wang, Y., & Ruedl, C. (2025) · Science Advances · doi:10.1126/sciadv.adq6038 · Cited by 67
“LD accumulation in macrophages can elevate their ROS production ( 9 , 11 ), promoting neurovascular dysfunction ( 67 ).”
An endothelial link between the benefits of physical exercise in dementia
Trigiani, L. J., & Hamel, É. (2017) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x17714655 · Cited by 69
“Other contributors to neuroinflammation are perivascular macrophages located adjacent to endothelial cells(92) that have recently been implicated in neurovascular dysfunction and cognitive impairments in a mouse model of chronic hypertension.(93) When perivascular macrophages were pharmacologically depleted in an AD m…”
BackgroundBi, Q., Wang, C., Cheng, G., Chen, N., Wei, B., Liu, X., Li, L., Lu, C. C., He, J., Weng, Y., et al. (2022) · Immunity · doi:10.1016/j.immuni.2022.06.018 · Cited by 66
Rajesh, A., Droho, S., & Lavine, J. A. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02562-3 · Cited by 65
“Collagen IV is a key component of the vascular sheath, which includes basement membranes from both endothelial cells on the luminal side and glial cells from the parenchyma [20].”
BackgroundA mechanistic survey of Alzheimer's disease
Tang, Y., Zhang, D., Gong, X., & Zheng, J. (2021) · Biophysical Chemistry · doi:10.1016/j.bpc.2021.106735 · Cited by 66
Czuba, E., Steliga, A., Lietzau, G., & Kowiański, P. (2017) · Metabolic Brain Disease · doi:10.1007/s11011-017-0015-3 · Cited by 62
The niche matters: Origin, function and fate of CNS-associated macrophages during health and disease
Dalmau Gasull, A., Glavan, M., Samawar, S. K. R., Kapupara, K., Kelk, J., Rubio, M., Fumagalli, S., Sorokin, L., Vivien, D., & Prinz, M. (2024) · Acta Neuropathologica · doi:10.1007/s00401-023-02676-9 · Cited by 60
“Interestingly, consistent with findings from AD studies, PvMΦ have been suggested to be responsible for the excessive production of ROS via Nox2 in mouse models of hypertension [28, 92].”
BackgroundWaste clearance shapes aging brain health
Jiang-Xie, L.-F., Drieu, A., & Kipnis, J. (2024) · Neuron · doi:10.1016/j.neuron.2024.09.017 · Cited by 66
“48 PBMs regulate CSF flow dynamics, but they also have additional essential functions in maintaining brain homeostasis, including participating in reactive oxygen species (ROS) signaling, 49 and regulating perivascular seeding of b -amyloid, 50 autoimmunity, 51 and hypertension.”
BackgroundAlzheimer’s dementia: pathogenesis and impact of cardiovascular risk factors on cognitive decline
Wanleenuwat, P., Iwanowski, P. S., & Kozubski, W. P. (2019) · Postgraduate Medicine · doi:10.1080/00325481.2019.1657776 · Cited by 58
“Perivascular macrophages are macrophages that reside in the perivascular space surrounding vessels of the brain, and through their generation of reactive oxygen species (ROS), can induce oxidative stress [63,64].”
BackgroundCheon, S. Y., & Song, J. (2022) · Cell & Bioscience · doi:10.1186/s13578-022-00836-0 · Cited by 58
Metadata
- Authors
- Faraco, G., Sugiyama, Y., Lane, D., Garcia-Bonilla, L., Chang, H., Santisteban, M. M., Racchumi, G., Murphy, M., Van Rooijen, N., Anrather, J., & Iadecola, C.
- Affiliations
- Weill Cornell Medicine (US)
- Corresponding author
- Iadecola, Costantino
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2016-11-14
- Volume
- 126
- Issue
- 12
- Pages
- 4674-4689
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC5127678
- OpenAlex
- W2552399604
- Semantic Scholar
- 0d40c3885f611fa0a162a7d2b301ccd4c8c8722e
- Cited by
- 350
- References
- 71
- Citations by year
- 2026: 34 · 2025: 39 · 2024: 47 · 2023: 39 · 2022: 43 · 2021: 31 · 2020: 34 · 2019: 36 · 2018: 26 · 2017: 20 · 2016: 1
- FWCI
- 15.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- American Heart Association (15SDG22760007)
- Fondation Leducq
- National Institutes of Health
- College of Veterinary Medicine, Cornell University
- National Institute of Neurological Disorders and Stroke (R37NS089323, R01NS095441)
- Topics
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- perivascular macrophages, hypertension, cognitive impairment, neurovascular regulation, blood-brain barrier permeability, angiotensin II, angiotensin II type 1 receptor, reactive oxygen species, NADPH oxidase 2, oxidative stress, cerebrovascular disease, dementia risk
- MeSH terms
- NADPH Oxidase 2, Angiotensin II, Animals, Blood-Brain Barrier, Disease Models, Animal, Hypertension, Macrophages, Male, Membrane Glycoproteins, Reactive Oxygen Species, Oxidative Stress, NADPH Oxidases, Receptor, Angiotensin, Type 1, Mice, Cognitive Dysfunction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
