Role of vascular muscle Peroxisome Proliferator‐Activated Receptor‐gamma (PPAR gamma) in the regulation of resistance vessel tone

Abstract

PPARγ is a ligand activated transcription factor expressed in vascular muscle and endothelium. We reported that targeted expression of a dominant negative PPARγ mutation in vascular muscle (S‐P467L) of transgenic mice caused hypertension and severe aortic dysfunction. Here, we hypothesized that PPARγ in vascular muscle plays a critical role in regulation of resistance vessel tone. Using a pressurized myograph, we observed mesenteric arteries (1o branch) from S‐P467L exhibited severely impaired relaxation to acetylcholine (1μM 22±6% S‐P467L vs 74±5% non‐transgenic (NT) littermate, P<0.05), but a normal response to sodium nitroprusside. We next measured the myogenic response in the 2o branch from S‐P467L mice compared to NT. Mesenteric arteries from S‐P467L exhibited markedly increased myogenic response compared to controls (at 100 mmHg: 33.6±2.5% in S‐P467L vs 16.9±1.9% in NT, P<0.05). The mRNA expression of transient receptor potential (TRP) channels, TRPC1, TRPC6 and TRPM4 did not differ between two groups. PKC inhibitors, chelerythrine chloride (3 μM) or calphostin C (10 nM) attenuated the myogenic response to a greater degree in S‐P467L than NT, whereas Y‐27632 (3 μM), a Rho kinase inhibitor, inhibited the myogenic response nearly equally in both groups. We conclude that interference with PPARγ in vascular muscle causes enhanced myogenic tone in mesenteric artery that is dependent upon PKC signaling.