Smooth Muscle-Targeted Overexpression Of Peroxisome Proliferator Activated Receptor-Gamma Disrupts Vascular Wall Structure And Function

Activation of the nuclear hormone receptor, PPAR., with pharmacological agonists promotes a contractile vascular smooth muscle cell phenotype and reduces oxidative stress and cell proliferation, particularly under pathological conditions including vascular injury, restenosis, and atherosclerosis. However, pharmacological agonists activate both PPAR gamma-dependent and -independent mechanisms in multiple cell types confounding efforts to clarify the precise role of PPAR gamma in smooth muscle cell structure and function in vivo. We, therefore, designed and characterized a mouse model with smooth muscle cell-targeted PPAR. overexpression (smPPAR gamma OE). Our results demonstrate that smPPAR gamma OE attenuated contractile responses in aortic rings, increased aortic compliance, caused aortic dilatation, and reduced mean arterial pressure. Molecular characterization revealed that compared to littermate control mice, aortas from smPPAR gamma OE mice expressed lower levels of contractile proteins and increased levels of adipocyte-specific transcripts. Morphological analysis demonstrated increased lipid deposition in the vascular media and in smooth muscle of extravascular tissues. In vitro adenoviral-mediated PPAR gamma overexpression in human aortic smooth muscle cells similarly increased adipocyte markers and lipid uptake. The findings demonstrate that smooth muscle PPAR gamma overexpression disrupts vascular wall structure and function, emphasizing that balanced PPAR gamma activity is essential for vascular smooth muscle homeostasis.