Smooth Muscle-Targeted Overexpression of Peroxisome Proliferator Activated Receptor-? Disrupts Vascular Wall Structure and Function.

ABSTRACT: 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?-dependent and -independent mechanisms in multiple cell types confounding efforts to clarify the precise role of PPAR? 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?OE). Our results demonstrate that smPPAR?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?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? overexpression in human aortic smooth muscle cells similarly increased adipocyte markers and lipid uptake. The findings demonstrate that smooth muscle PPAR? overexpression disrupts vascular wall structure and function, emphasizing that balanced PPAR? activity is essential for vascular smooth muscle homeostasis.

SUBMITTER: Kleinhenz JM 

PROVIDER: S-EPMC4599849 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature