Abstract P205: Endothelium-specific Interference with PPARG Causes Cerebral Vascular Dysfunction in Response to Endogenous Renin-angiotensin System Activation

Abstract

Abnormal activation of the endogenous renin-angiotensin system (RAS) has been implicated in various cardiovascular (CV) disorders including hypertension, atherosclerosis and stroke. Whereas a low salt diet may be beneficial in salt-sensitive hypertension, it has been proposed to also cause CV risk due to activation of the RAS. The molecular mechanism by which RAS activation mediates vascular dysfunction remains undefined. Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor which activates anti-oxidant and anti-inflammatory processes and can regulate the actions of angiotensin II (AngII) in the vasculature. We examined endothelial function in transgenic mice specifically expressing dominant-negative (DN) mutations in PPARγ in the endothelium (E-V290M) fed a low salt diet to test the hypothesis that endothelial PPARγ plays a protective role in the vasculature in response to endogenous RAS activation. Circulating levels of renin were significantly increased in both non-transgenic (NT) and E-V290M mice fed a low-salt diet for 6 weeks compared to standard chow (NT: 39.3±7.4 vs 19.8±1.3 ng/ml; E-V290M: 34.3±0.8 vs 16.0±3.8 ng/ml, p<0.05, n=5). Under baseline conditions, responses to endothelium-dependent agonist acetylcholine were not affected in E-V290M mice compared to NT (basilar artery: 66.1±11.8 vs 63.5±3.7%; carotid artery: 93.3±3.6 vs 91.1±4.2%, n=5). Six weeks of low-salt diet significantly impaired acetylcholine-mediated dilation in the basilar artery of E-V290M mice but not in NT (41.7±7.7 vs 74.2±5.0%, p<0.05, n=5). Unlike basilar artery, 6 weeks of low salt diet was not sufficient to induce vascular dysfunction in carotid artery or aorta of E-V290M mice (carotid artery: 85.6±4.4 vs 91.9±2.5%, n=5; aorta: 80.8±5.4 vs 87.0±5.6%, n=3). The responses to endothelium-independent vasodilator sodium nitroprusside (SNP) were not different in E-V290M mice compared to NT controls. We conclude that endothelial-specific interference with PPARγ causes endothelial dysfunction in response to endogenous RAS activation induced by a low-salt diet. Moreover, the cerebral circulation is particularly susceptible to low salt diet-induced dysfunction in conjunction with PPARγ impairment.