平滑肌线粒体膜电位超极化致血管功能障碍在肥胖相关高血压中的作用及机制

The incidence of hypertension is nearly 50% in obese patients. However, with energy control such as diet limitation or physical exercise, the blood pressure of obese patients is significantly decreased even before weight loss, which indicates that there is a tight relationship between metabolism and blood pressure. Recently, we found that mitochondria play an important role in the regulation of vascular tone: metabolism could induce vasoconstriction via mitochondrial membrane potential (△Ψm) hyperpolarization of vascular smooth muscle cells. It is not clear whether this phenomenon is involved in obesity related hypertension. This study is designed to explore the role of △Ψm in obesity related vascular dysfunction and hypertension. Firstly, △Ψm of vascular smooth muscle cells in obese patients and mice will be measured by combination of vascular vitro perfusion and confocal detection technology, and the relationship between △Ψm, vascular dysfunction and hypertension will be analysed. Moreover, MLCK and ROCK pathway which mediate vascular smooth muscle cell contraction will be observed to find the key molecules in vascular regulation by △Ψm. Finally, diet limitation or aerobic exercise is used to find if △Ψm decreasing could alleviate obesity related vascular dysfunction and postpone high blood pressure progress. This study will elucidate the pathogenesis of obesity related hypertension from metabolic view and will provide a new theory for its prevention and treatment.

肥胖患者高血压发病率将近50%，而采取能量控制的方式如减少饮食或增加锻炼后，肥胖患者的血压在体重未发生明显改变之前即显著下降，这提示能量代谢与血压之间有密切联系。我们新近发现平滑肌线粒体在调节血管张力中发挥重要作用：代谢通过血管平滑肌细胞线粒体膜电位（△Ψm）超极化引起血管收缩。但上述发现是否参与肥胖相关高血压尚不清楚。本研究拟①利用血管离体灌流同步激光共聚焦技术，检测肥胖患者和肥胖小鼠中血管平滑肌细胞△Ψm的改变情况，分析其与血管功能障碍及高血压的相关性；②检测调控血管平滑肌细胞收缩的主要信号MLCK通路和ROCK通路的变化，寻找受△Ψm调控的靶分子；③进一步探究限制饮食或有氧运动对肥胖小鼠血管平滑肌△Ψm、血管功能及血压的影响。本研究有望从代谢角度揭示肥胖相关高血压的新机制，为其防治提供新思路。

肥胖患者高血压发病率居高不下，这提示能量代谢与血压之间有密切联系。我们前期发现平滑肌线粒体在调节血管张力中发挥重要作用：高糖刺激通过血管平滑肌细胞△Ψm超极化引起血管收缩。本课题旨在揭示△Ψm超极化引起血管收缩的具体机制，以及高血压△Ψm超极化的原因。通过本研究我们发现：①高糖刺激通过血管平滑肌△Ψm超极化引起血管收缩的主要机制是ROCK-MLCP途径；②在血管紧张素II引起的高血压大鼠模型中，发现平滑肌细胞Bcl-xL解偶联线粒体现象介导高血压的发生发展，而外泌体miR-140-5p参与上述调节过程。本研究从代谢角度揭示高血压发生发展的新机制，为其防治及靶向治疗提供新的思路。