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Activation of the Central Renin-Angiotensin System Causes Local Cerebrovascular Dysfunction. Stroke 2021 07;52(7):2404-2413

Date

06/11/2021

Pubmed ID

34107734

Pubmed Central ID

PMC8262118

DOI

10.1161/STROKEAHA.121.034984

Scopus ID

2-s2.0-85111789053   2 Citations

Abstract

Background and Purpose: Hypertension is a leading risk factor for cerebrovascular disease and loss of brain health. While the brain renin-angiotensin system (RAS) contributes to hypertension, its potential impact on the local vasculature is unclear. We tested the hypothesis that activation of the brain RAS would alter the local vasculature using a modified deoxycorticosterone acetate (DOCA) model.

Methods: C57BL/6 mice treated with DOCA (50 mg SQ; or shams) were given tap H2O and H2O with 0.9% NaCl for 1 to 3 weeks.

Results: In isolated cerebral arteries and parenchymal arterioles from DOCA-treated male mice, endothelium- and nitric oxide-dependent dilation was progressively impaired, while mesenteric arteries were unaffected. In contrast, cerebral endothelial function was not significantly affected in female mice treated with DOCA. In males, mRNA expression of renal Ren1 was markedly reduced while RAS components (eg, Agt and Ace) were increased in both brain and cerebral arteries with central RAS activation. In NZ44 reporter mice expressing GFP (green fluorescent protein) driven by the angiotensin II type 1A receptor (Agtr1a) promoter, DOCA increased GFP expression a??3-fold in cerebral arteries. Impaired endothelial responses were restored to normal by losartan, an AT1R (angiotensin II type 1 receptor) antagonist. Last, DOCA treatment produced inward remodeling of parenchymal arterioles.

Conclusions: These findings suggest activation of the central and cerebrovascular RAS impairs endothelial (nitric oxide dependent) signaling in brain through expression and activation of AT1R and sex-dependent effects. The central RAS may be a key contributor to vascular dysfunction in brain in a preclinical (low renin) model of hypertension. Because the brain RAS is also activated during aging and other diseases, a common mechanism may promote loss of endothelial and brain health despite diverse cause.

Author List

De Silva TM, Modrick ML, Grobe JL, Faraci FM

Author

Justin L. Grobe PhD Associate Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cerebrovascular Disorders
Desoxycorticosterone Acetate
Endothelium, Vascular
Female
Hypertension
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Nitric Oxide Synthase Type III
Receptor, Angiotensin, Type 1
Renin-Angiotensin System