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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.
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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.
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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
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“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
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- 10.1152/ajpheart.00679.2010 · DOI · Paper page
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Items 301–344 of 344
Research Progress of Vascular Cognitive Impairment
宫, 嵘. (2021) · Advances in Clinical Medicine · doi:10.12677/acm.2021.1112854 · Cited by 1
Recent topics regarding macrophage in the central nervous system
Masuda, T. (2022) · The Journal of Biochemistry · doi:10.1093/jb/mvac093 · Cited by 1
No energy wasted in the fight against vascular inflammation
Crowley, S. D. (2018) · Cardiovascular Research · doi:10.1093/cvr/cvy232 · Cited by 1
The Association between Glymphatic System and Perivascular Macrophages in Brain Waste ClearancePreprint
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Discovery of novel blood-brain barrier neuropathology in schizophrenia and bipolar disorder midbrainPreprint
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Blood pressure variability compromises vascular function in middle-aged micePreprint
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“…and anesthetized by isoflurane inhalation (5% induction, 2% maintenance) for subcutaneous (s.c.) implantation of an osmotic minipump (ALZET model 2006, DURECT Corporation) containing either saline (sham-operated control) or AngII (600ng/kg/min; Sigma-Aldrich, A9525), as previously described 20,22 .”
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“Microglia, the resident immune cells of the central nervous system (CNS), are highly sensitive to changes in systemic inflammatory and metabolic states (13-15).”
Cerebral Vascular Biology in Health and Disease
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“Non-parenchymal brain macrophages are mononuclear phagocytes that are increasingly recognized to be critical players in the diseases of the central nervous system [25-28].”
BackgroundAngiotensin II and its action within the brain during hypertension
Sriramula, S., & Biancardi, V. C. (2023) · Elsevier eBooks · doi:10.1016/b978-0-323-99618-1.00017-9
Blood pressure variability compromises vascular function in middle-aged micePreprint
Mendiola, P. J., O’Herron, P. J., Xie, K., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.10.21.619509
Orieux, A., Boulestreau, R., Bats, M., Michot, M., Boyer, A., Dinet, V., Vaurs, J., Dufourcq, P., Peghaire, C. R., Duplàa, C., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.03.24.641145
Qian, Y., Lin, X., Wang, Y., Mao, Y., Zou, T., & Zhang, L. (2025) · Survey of Ophthalmology · doi:10.1016/j.survophthal.2025.08.010
Blood pressure variability compromises vascular function in middle-aged micePreprint
Mendiola, P. J., O’Herron, P. J., Xie, K., Brands, M. W., Bush, W., Patterson, R., Stefano, V. D., & Filosa, J. A. (2025) · eLife · doi:10.7554/elife.104082.2
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“In C57BL/6J, in response to low-dose AngII infusion, we observe a low-grade, controlled inflammatory profile (characterized by microglial activation and perivascular macrophage recruitment), associated with preserved BBB integrity, and suggesting a strain-specific neurovascular phenotype 31 .”
Hypertension and brain damage: evidence from rodent models
Scenna, M. S., Maceroni, E., Cimini, A., Castelli, V., & d’Angelo, M. (2026) · Laboratory Animal Research · doi:10.1186/s42826-026-00270-0
“…studies have shown that neurovascular coupling to whisker stimulation is compromised in genetic models of persistent hypertension, such as BPH/2J [67] and SHR. Notably, this dysfunction emerged even in the absence of changes in neuronal viability markers, suggesting that vascular dysregulation…”
InfluentialUnderstanding the role of perivascular macrophages in Parkinson's disease pathophysiology
Fuentealba, J. R. (2017) · theses.fr (ABES) · doi:10.70675/b2e8f905z4f72z497eza017zc5b9d7fe53a1
“It was previously shown that PVMs populate mostly pial and parenchymal vessels larger than 10μm in diameter (Faraco et al., 2016).”
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Engulfment by brain macrophages in a short-lived vertebratePreprint
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A perivascular perspective on the immune impacts in cerebral amyloid angiopathy
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The gut–brain axis: mechanisms linking intestinal dysbiosis with stroke
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“Moreover, BAMs, especially PVMs, influence not only stroke response but also stroke risk by contributing to neurovascular dysfunction in hypertension, the major risk factor for stroke (Faraco et al., 2016).”
Argenti, L., Cirone, A., Massa, F., Sentieri, E., Losa, M., Lorenzini, L., Garbarino, S., Sofia, L., Raffa, S., Bauckneht, M., et al. (2026) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.70390
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“…meningeal and perivascular mast cells modulate BBB permeability and neuroinflammatory responses through the release of histamine, cytokines (e.g., TNF-α , IL-1 β ), proteases (e.g., tryptase, chymase), and other vasoactive mediators (Faraco et al., 2016; Theoharides, 2017; Skaper et al., 2014).”
What Is the Role of Endothelial Cells in Cerebral Blood Flow Dysregulation in Small Vessel Disease?
Benarroch, E. E. (2026) · Neurology · doi:10.1212/wnl.0000000000218477
Brain macrophages in neurodegeneration
Johnston, R. J., Torres, N. A. P., Li, Y., & Han, C. Z. (2026) · Advances in immunology · doi:10.1016/bs.ai.2026.06.005 · Cited by 1
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Engulfment by brain macrophages in a short-lived vertebratePreprint
Nagvekar, R., Pogson, A. N., Kalakuntla, P. R., Barr, H. J., Jaimes, A. M. M., Perry, S., Costa, E. K., Chen, J., Boos, F., Negredo, P. N., et al. (2026) · eLife · doi:10.7554/elife.112503.1
Engulfment by brain macrophages in a short-lived vertebratePreprint
Nagvekar, R., Pogson, A. N., Kalakuntla, P. R., Barr, H. J., Jaimes, A. M. M., Perry, S., Costa, E. K., Chen, J., Boos, F., Negredo, P. N., et al. (2026) · eLife · doi:10.7554/elife.112503
林艳雅, Lin, C., Chen, J., Chen, S., Huang, J., & Hu, J. (2026) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2026.1863509
“…evidence implicates PVMs in neurovascular pathology across multiple disease contexts, including hypertension-associated cognitive dysfunction (Faraco et al., 2016), amyloid clearance in cerebral amyloid angiopathy (Hawkes and McLaurin, 2009), and dynamic responses to ischemic vascular injury…”
Longden, T. A., Vigderman, A. S., Ju, S., & Isaacs, D. P. (2026) · Hypertension · doi:10.1161/hypertensionaha.126.26766
Vascular cognitive impairment and dementia: current understanding and future directions
Garg, S., & McCullough, L. D. (2026) · npj Dementia · doi:10.1038/s44400-026-00135-2
“Depletion of PVMs or blockade of angiotensin II receptors in hypertensive models rescues endothelial function and normalizes CBF, highlighting a critical immune-vascular interface in hypertension-induced cognitive impairment 81,82 .”
RNA interference in neurological disorders: Silencing harmful immune responses
Farhan, M., Islam, M. S., Srivastava, Y., Singh, J., Khan, H., & Zhang, Q. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-44631-3.00013-5
Matsumura, S., Moriyama, Y., Ochiai, A., Iwatani, Y., Hayashi, H., & Takagi, N. (2026) · Neurochemical Research · doi:10.1007/s11064-026-04881-w
“Previous studies have demonstrated that intracerebroventricular injection of CLO depletes PVM-enriched macrophage populations without affecting microglia or astrocytes in the brain parenchyma [20], and that PVMs depletion occurs within 3–7 days after the injec - tion [17, 21 ].”
Chronic Hypertension and the Brain’s Waste Drainage System
Alian, M., Le, C., Williams, A., Wardlaw, J. M., & Benveniste, H. (2026) · Hypertension · doi:10.1161/hypertensionaha.126.26767
From endovascular therapy to perivascular therapy: A new concept and perspective
Wang, Z., Shi, P., Zhou, Y.-J., Guo, W., Cao, Y., Mao, S., & Teng, G.-J. (2026) · EngMedicine · doi:10.1016/j.engmed.2026.100164
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
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