Abstract
Abstract WMP109: Activation of the Brain Renin-Angiotensin System (RAS) Causes Selective Cerebrovascular Dysfunction
Stroke (1970), Vol.47(suppl_1)
02/2016
DOI: 10.1161/str.47.suppl_1.wmp109
Abstract
Hypertension is a leading risk factor for cerebrovascular disease. Although many changes during hypertension may be mediated by the RAS, most hypertensive patients have normal or reduced levels of circulating renin, suggesting that local tissue RAS play a key role. Surprisingly, little is known regarding the impact of the brain RAS on the cerebral vasculature. We tested the hypothesis that activation of the central RAS using deoxycorticosterone (DOCA)-salt (which simultaneously suppresses the peripheral RAS) alters vascular function. Male C57Bl/6 mice treated with DOCA were given both tap water and water with 0.9% salt for 3 weeks, followed by measurements of vessel reactivity. Mean arterial pressure was elevated modestly after DOCA-salt (79±2 vs 95±3 mmHg; P<0.01). In DOCA-salt treated mice, endothelium-dependent dilation of isolated middle cerebral arteries was almost abolished compared to shams, whereas dilation in mesenteric arteries was normal. This striking effect in brain extended to small parenchymal arterioles. Endothelium-independent vasodilation was similar in all groups. Analysis of mRNA revealed that expression of renal renin was markedly reduced by DOCA-salt while expression of RAS components (eg, AGT, ACE) were increased in both brain and cerebral arteries. In NZ44 reporter mice that express GFP driven by the angiotensin II type 1A receptor (AT1AR) promoter, DOCA-salt significantly increased AT1R-GFP protein expression in cerebral arteries. In cerebral arterioles in vivo, local inhibition of AT1R, mineralocorticoid receptors (MR), or Rho kinase (including ROCK2) reversed endothelial dysfunction in DOCA-salt treated mice. These findings suggest for the first time that activation of the brain and the cerebrovascular RAS profoundly, but selectively, impairs vascular function in brain. Our findings identify AT1R, MR and Rho kinase as key contributors to vascular dysfunction in brain in a clinically relevant model of hypertension.
Details
- Title: Subtitle
- Abstract WMP109: Activation of the Brain Renin-Angiotensin System (RAS) Causes Selective Cerebrovascular Dysfunction
- Creators
- Travice M De Silva - University of IowaJustin Grobe - University of IowaFrank M Faraci - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Stroke (1970), Vol.47(suppl_1)
- DOI
- 10.1161/str.47.suppl_1.wmp109
- ISSN
- 0039-2499
- eISSN
- 1524-4628
- Language
- English
- Date published
- 02/2016
- Academic Unit
- Cardiovascular Medicine; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984304002502771
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