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

Activation of the nuclear hormone receptor, PPARγ, 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 PPARγ-dependent and -independent mechanisms in multiple cell types confounding efforts to clarify the precise role of PPARγ in smooth muscle cell structure and function in vivo. We, therefore, designed and characterized a mouse model with smooth muscle cell-targeted PPARγ overexpression (smPPARγOE). Our results demonstrate that smPPARγOE 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 smPPARγOE 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 PPARγ overexpression in human aortic smooth muscle cells similarly increased adipocyte markers and lipid uptake. The findings demonstrate that smooth muscle PPARγ overexpression disrupts vascular wall structure and function, emphasizing that balanced PPARγ activity is essential for vascular smooth muscle homeostasis.

采用药理学激动剂激活核激素受体过氧化物酶体增殖物激活受体γ（PPARγ），可促进血管平滑肌细胞的收缩表型，并减轻氧化应激与细胞增殖，在血管损伤、再狭窄及动脉粥样硬化等病理状态下该效应尤为显著。
然而，药理学激动剂可在多种细胞类型中同时激活PPARγ依赖与非依赖通路，这使得学界难以阐明PPARγ在体内平滑肌细胞结构与功能中的确切作用。
为此，我们构建并鉴定了一种平滑肌细胞特异性过表达PPARγ的小鼠模型（smPPARγOE）。
研究结果显示，smPPARγOE小鼠的主动脉环收缩反应减弱，主动脉顺应性提升，主动脉出现扩张，且平均动脉压降低。
分子生物学特征分析显示，与同窝对照小鼠相比，smPPARγOE小鼠的主动脉中收缩蛋白表达水平更低，而脂肪细胞特异性转录本的表达水平升高。
形态学分析表明，smPPARγOE小鼠的血管中层及血管外组织的平滑肌中脂质沉积增多。
在体外实验中，腺病毒介导的人主动脉平滑肌细胞PPARγ过表达同样提升了脂肪细胞标志物的表达水平，并增强了脂质摄取能力。
本研究结果证实，平滑肌PPARγ过表达会破坏血管壁的结构与功能，这表明PPARγ活性的稳态平衡对于维持血管平滑肌内环境稳态至关重要。