Interference with peroxisome proliferator activated receptor gamma function in smooth muscle causes vascular dysfunction and hypertension

Peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the nuclear receptor superfamily of ligand activated transcription factors, plays a critical role in adipogenesis and lipid metabolism. Thiazolidinediones are high affinity ligands of PPARgamma which target insulin utilizing tissues such as adipose tissue and skeletal muscle and are used to treat type II diabetes. Mutations in PPARgamma cause type II diabetes and severe hypertension suggesting that PPARgamma also plays an important role in the cardiovascular system. We tested the hypothesis that PPARgamma in vascular muscle plays a central role in the regulation of vascular tone and structure and that interference with PPARgamma function in vascular muscle will cause vascular dysfunction, vascular hypertrophy and hypertension. We developed transgenic mice expressing the dominant negative mutations in PPARgamma that were previously shown to cause diabetes and hypertension in humans, under the control of a smooth muscle-specific promoter. We show that interference with PPARgamma causes a loss of responsiveness to nitric oxide and cGMP and striking alterations in contractility in the aorta. Interference with PPARgamma also causes isolated systolic hypertension and hypertrophy and inward remodeling in the cerebral microcirculation. The results identify PPARgamma as playing a critical role in vascular muscle as a regulator of vascular structure and function and blood pressure.