The cerebrovascular dysfunction induced by slow pressor doses of angiotensin II precedes the development of hypertension
Open accessAbstract
Hypertension alters cerebrovascular regulation and increases the brain's susceptibility to stroke and dementia. We investigated the temporal relationships between the arterial pressure (AP) elevation induced by “slow pressor” angiotensin II (ANG II) infusion, which recapitulates key features of human hypertension, and the resulting cerebrovascular dysfunction. Minipumps delivering saline or ANG II for 14 days were implanted subcutaneously in C57BL/6 mice ( n = 5/group). Cerebral blood flow was assessed by laser-Doppler flowmetry in anesthetized mice equipped with a cranial window. With ANG II (600 ng·kg−1·min−1), AP started to rise after 9 days ( P < 0.05 vs. saline), remained elevated at 11–17 days, and returned to baseline at 21 days ( P > 0.05). ANG II attenuated the cerebral blood flow increase induced by neural activity (whisker stimulation) or endothelium-dependent vasodilators, an effect observed before the AP elevation (7 days), as well as after the hypertension subsided (21 days). Nonpressor doses of ANG II (200 ng·kg−1·min−1) induced cerebrovascular dysfunction and oxidative stress without elevating AP ( P > 0.05 vs. saline), whereas phenylephrine elevated AP without inducing cerebrovascular effects. ANG II (600 ng·kg−1·min−1) augmented neocortical reactive oxygen species (ROS) with a time course similar to that of the cerebrovascular dysfunction. Neocortical application of the ROS scavenger manganic(I-II)meso-tetrakis(4-benzoic acid)porphyrin or the NADPH oxidase peptide inhibitor gp91ds-tat attenuated ROS and cerebrovascular dysfunction. We conclude that the alterations in neurovascular regulation induced by slow pressor ANG II develop before hypertension and persist beyond AP normalization but are not permanent. The findings unveil a striking susceptibility of cerebrovascular function to the deleterious effects of ANG II and raise the possibility that cerebrovascular dysregulation precedes the elevation in AP also in patients with ANG II-dependent hypertension.
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Blood-brain barrier permeability tended to rise before hypertension onset, similar to the cerebrovascular dysfunction first seen 7 days after angiotensin II administration.
“BBB permeability tended to increase before the onset of hypertension, like the cerebrovascular dysfunction, which is first observed 7 days after ANGII administration (54).”
From Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension (2016) · cites this paper as [54]
ANGII increases the ROS signal in PVMs.
“As illustrated in Figure 7B, ANGII induces an increase in ROS signal, assessed by hydroethidine microfluorography (10,35) in PVMs.”
From Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension (2016) · cites this paper as [35]
The fluorescent signal produced by hydroethidine oxidation products indicates cumulative reactive oxygen species production.
“The fluorescence signal attributable to HE oxidation products reflects cumulative ROS production (35).”
From Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension (2016) · cites this paper as [35]
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- Authors
- Capone, C., Faraco, G., Park, L., Cao, X., Davisson, R. L., & Iadecola, C.
- Affiliations
- Division of Neurobiology, Department of Neurology and Neuroscience, and
- Weill Cornell Medicine (US)
- Cornell University (US)
- Corresponding author
- Iadecola, Costantino
- Venue
- American Journal of Physiology-Heart and Circulatory Physiology
- Publisher
- American Physiological Society
- Published
- 2011-01
- Volume
- 300
- Issue
- 1
- Pages
- H397-H407
- ISSN
- 0363-6135 (ISSN-L)
- 1522-1539
- PMC
- PMC3023263
- OpenAlex
- W2118435546
- Cited by
- 136
- References
- 41
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 7 · 2023: 6 · 2022: 9 · 2021: 8 · 2020: 10 · 2019: 7 · 2018: 7 · 2017: 8 · 2016: 12 · 2015: 8 · 2014: 9 · 2013: 12 · 2012: 14
- FWCI
- 6.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL-96571, R01HL063887, P01HL096571)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- angiotensin II, hypertension, cerebrovascular dysfunction, cerebral blood flow, arterial pressure, oxidative stress, reactive oxygen species, NADPH oxidase, gp91phox, neurovascular coupling, whisker stimulation, endothelium-dependent vasodilation, C57BL/6 mice
- MeSH terms
- Analysis of Variance, Angiotensin II, Animals, Blood Pressure, Cerebrovascular Circulation, Electrophysiology, Evoked Potentials, Hypertension, Immunohistochemistry, Infusion Pumps, Mice, Inbred C57BL, Telemetry, Time Factors, Vasoconstrictor Agents, Vibrissae, Laser-Doppler Flowmetry, Reactive Oxygen Species, Oxidative Stress, Mice
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