Genetic interference with peroxisome proliferator‐activated receptor γ (PPARγ) in smooth muscle enhances cerebrovascular myogenic tone via a rho kinase‐dependent mechanism

Abstract

Cerebral arteries are important resistance vessels and play a crucial role in regulating cerebral blood flow (CBF). Myogenic responses are a key element of mechanisms that regulate CBF during altered perfusion pressure. PPARγ may play a protective role in the vasculature by inhibiting increases in vascular tone. We tested whether cell‐specific interference with PPARγ in smooth muscle would increase myogenic tone in cerebral arteries. We studied mice expressing a dominant negative mutation of human PPARγ in smooth muscle (TG) and littermate controls (NT). Under baseline conditions (75 mmHg), middle cerebral arteries (MCA) from TG mice generated more myogenic tone compared with arteries from NT (31±4% vs. 9±2% of max diameter n=7–8). Myogenic reactivity was augmented in MCA from TG mice over a range of pressures (15–150 mmHg) compared with NT whereas diameter in Ca2+ free conditions was similar between groups. Treatment of MCA from TG mice with the rho kinase inhibitor Y27632 abolished the augmentation of myogenic tone (34±5% vs. 9±4% of max diameter n=7). Treatment of vessels from TG with the superoxide dismutase mimetic tempol reduced myogenic tone by ~30% (33±4% vs. 21±2% of max diameter n=6). These findings suggest that PPARγ in vascular muscle regulates rho kinase, influencing myogenic tone in small resistance arteries. This work was supported by NIH grants NS24621 and HL62984 and AHA Fellowship 12POST9150027.