PPARγ Regulates Resistance Vessel Tone Through a Mechanism Involving RGS5-Mediated Control of Protein Kinase C and BKCa Channel Activity

Rationale: Activation of peroxisome proliferator-activated receptor-gamma (PPAR gamma) by thiazolidinediones lowers blood pressure, whereas PPAR gamma mutations cause hypertension. Previous studies suggest these effects may be mediated through the vasculature, but the underlying mechanisms remain unclear. Objective: To identify PPAR gamma mechanisms and transcriptional targets in vascular smooth muscle and their role in regulating resistance artery tone. Methods and Results: We studied mesenteric artery (MA) from transgenic mice expressing dominant-negative (DN) mutant PPAR gamma driven by a smooth muscle cell-specific promoter. MA from transgenic mice exhibited a robust increase in myogenic tone. Patch clamp analysis revealed a reduced large conductance Ca2+-activated K+ (BKCa) current in freshly dissociated smooth muscle cell from transgenic MA. Inhibition of protein kinase C corrected both enhanced myogenic constriction and impaired the large conductance Ca2+-activated K+ channel function. Gene expression profiling revealed a marked loss of the regulator of G protein signaling 5 (RGS5) mRNA in transgenic MA, which was accompanied by a substantial increase in angiotensin II-induced constriction in MA. Small interfering RNA targeting RGS5 caused augmented myogenic tone in intact mesenteric arteries and increased activation of protein kinase C in smooth muscle cell cultures. PPAR gamma and PPAR delta each bind to a PPAR response element close to the RGS5 promoter. RGS5 expression in nontransgenic MA was induced after activation of either PPAR gamma or PPAR delta, an effect that was markedly blunted by DN PPAR gamma. Conclusions: We conclude that RGS5 in smooth muscle is a PPAR gamma and PPAR delta target, which when activated blunts angiotensin II-mediated activation of protein kinase C, and preserves the large conductance Ca2+-activated K+ channel activity, thus providing tight control of myogenic tone in the microcirculation. (Circ Res. 2012;111:1446-1458.)