PGC1α regulates the mitochondrial metabolism response to cyclic stretch, which inhibits neointimal hyperplasia

PGC1α regulates the mitochondrial metabolism response to cyclic stretch, which inhibits neointimal hyperplasia microscopy revealed that intimal injury disrupted the balance of vascular energy metabolism and impaired the mitochondrial ultrastructure in vivo. The human carotid plaque and femoral artery plaque samples also exhibited alterations in mitochondrial morphology. Vascular smooth muscle cells (VSMCs) are the main components of neointimal hyperplasia and are subjected to cyclic stretch resulting from pulsatile pressure. In this study, we found that the application of cyclic stretch in vitro increased VSMC mitochondrial mass and function. In addition, peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α) played an important role in regulating VSMC mitochondrial function in response to physiological stretch via the phosphorylation of Smad3. Increasing the activation of PGC1α by ZLN005 treatment effectively inhibited VSMC hyperproliferation after intimal injury in vivo. These results suggested that the regulation of PGC1α by p-Smad3 in response to physiological cyclic stretch may effectively alleviate neointimal hyperplasia by promoting mitochondrial function. PGC1α may be a potential therapeutic target for the prevention and treatment of neointimal hyperplasia.过氧化物酶体增殖物激活受体γ辅激活因子1α（PGC1α）可介导应对周期性牵张的线粒体代谢调控通路，其活性能够抑制新生内膜增生。体内显微成像研究显示，内膜损伤会破坏血管能量代谢平衡，并损伤线粒体超微结构。人类颈动脉斑块与股动脉斑块样本同样存在线粒体形态异常改变。血管平滑肌细胞（vascular smooth muscle cells, VSMCs）是新生内膜增生的核心组成细胞，且会受到搏动压力诱导的周期性牵张刺激。本研究发现，体外施加周期性牵张可提升VSMC的线粒体质量与功能水平。此外，过氧化物酶体增殖物激活受体γ辅激活因子1α（PGC1α）可通过Smad3磷酸化途径，在调控VSMC响应生理性牵张的线粒体功能过程中发挥关键作用。经ZLN005处理以增强PGC1α的激活效果，可有效抑制体内内膜损伤后VSMC的过度增殖。上述结果表明，磷酸化Smad3（p-Smad3）响应生理性周期性牵张对PGC1α的调控作用，可通过促进线粒体功能有效缓解新生内膜增生。PGC1α或可成为预防与治疗新生内膜增生的潜在治疗靶点。