Abstract P242: Microvascular Changes in Brain During Salt-sensitive Hypertension: Molecular Mechanisms and Implications for Small Vessel Disease

Abstract

Hypertension is a major risk factor for small vessel disease (SVD), a leading contributor to stroke and dementias. Mechanisms that underlie SVD in brain are poorly defined, with no specific therapy at present. Because parenchymal and pial arterioles are targets of the SVD process, we examined microvascular changes in a model using deoxycorticosterone-salt (DOCA) to activate the brain renin-angiotensin system (RAS), with resulting salt-sensitive (sodium- and fluid-dependent) hypertension. Male C57Bl/6 mice were treated with DOCA and given the choice of drinking H 2 O or H 2 O with 0.9% NaCl for 3 wks. Along with a modest elevation in mean arterial pressure (79±2 vs 95±3 mmHg, P<0.05), DOCA impaired endothelium-dependent dilation of both isolated parenchymal (baseline diameter of 15±1 μm) and pial arterioles (37±1 μm) in a pathway specific manner. Endothelium-dependent hyperpolarization was intact while eNOS-mediated vasodilation was markedly impaired along with reductions in phosphorylation in AKT (an upstream activator of eNOS). Local inhibition of angiotensin II type 1 (AT1-R) or mineralocorticoid receptors (MR) or Rho kinase (including ROCK2), restored endothelial function in DOCA-treated mice. Inner diameter of maximally dilated parenchymal arterioles was reduced approximately 20% by DOCA (P<0.05 vs sham). DOCA increased mRNA expression of RAS components (eg, AGT, ACE) in both brain and cerebral vessels. In NZ44 reporter mice that express GFP driven by the AT1A-R promoter, DOCA increased cerebrovascular GFP protein expression about 3-fold (P<0.05). Thus, DOCA activates both the brain and the cerebrovascular RAS, impairs select pathways affecting parenchymal and pial arteriolar function, while producing inward microvascular remodeling. AT1R, MR and ROCK2 are key contributors to cerebral microvascular dysfunction in this clinically relevant model of SVD.