Abstract 661: Genetic Interference with Peroxisome Proliferator-Activated Receptor Gamma in Vascular Muscle Impairs Cerebrovascular Responses to Nitric Oxide and Enhances Myogenic Tone Via a Rho Kinase-Dependent Mechanism

Abstract

Cerebral arteries are important resistance vessels in brain and play a crucial role in regulating cerebral blood flow. Nitric oxide (NO) plays a major role in the cerebral circulation influencing vascular structure and blood flow, mediating endothelium-dependent vasodilation, and contributing to neurovascular coupling. Peroxisome proliferator-activated receptor-gamma (PPARγ) is a transcription factor that may play a protective role in the vasculature by enhancing NO signaling and inhibiting increases in vascular tone. We tested whether cell-specific interference with PPARγ in smooth muscle would alter responses to NO and increase myogenic tone in cerebral arteries. We studied mice expressing either a dominant negative mutation of human PPARγ (P467L) or increased expression of WT PPARγ (S-WT) in smooth muscle (S-P467L). In basilar arteries, vasodilation to nitroprusside (NO donor) was markedly impaired in S-P467L compared with S-WT or non-transgenic mice (NT) (e.g. 1 μM nitroprusside: NT, 60±6% vs. S-WT, 63±2% vs. S-P467L, 16±3%, n=6-11). As PPARγ may suppress rho kinase signaling, we examined its role in regulating responses to NO. Impaired vasodilation to nitroprusside in S-P467L mice were restored to normal by an inhibitor of rho kinase (Y27632, 3 μM). Angiotensin II (Ang II) activates rho kinase via AT1 receptors. As AT1-mediated effects may also be suppressed by PPARγ, we examined effects of an AT1 receptor antagonist (losartan). Losartan (1 μM) completely inhibited vasoconstriction to Ang II and increased responses to nitroprusside to ∼70% of normal in S-P467L mice. In response to intraluminal pressure (75 mmHg), middle cerebral arteries (MCA) from S-P467L mice constricted 31±4% compared with 9±2% for NT (n=7-8). Dilation of MCA from S-P467L mice to acetylcholine was significantly impaired compared with controls, whereas dilation to papaverine was similar between genotypes. Treatment of the MCA from S-P467L mice with Y27632 abolished the augmentation of myogenic tone (control, 34±5% vs. Y27632, 9±4%, n=7). These findings suggest that PPARγ in vascular muscle normally inhibits rho kinase, influencing responses to NO and myogenic tone in small resistance arteries.