胃肠转流术激活TRPA1调控血管稳态降低血压的机制

Gastrointestinal homeostasis plays an important factor in cardiovascular and metabolic diseases. Gastrointestinal intervention can effectively prevent cardiometabolic dysfunction, however its mechanism is little known. Our previous studies showed that Roux-en-Y gastric bypass surgery lowered blood pressure and inhibited sympathetic activation, but the mechanism is unclear. The transient receptor potential ankyrin 1 (TRPA1) channel is a gastrointestinal mucous membrane receptor which can be activated by gastrointestinal environment and transmits some inhibitory signal to regulatory central of blood pressure through the splanchnic nerve. We found that TRPA1 was mainly distributed in perivascular adventitia and intestinal mucosa, and participated in the neural regulation of blood vessel. We propose a hypothese that change of gastrointestinal environment by Roux-en-Y gastric bypass surgery may activate TRPA1 on enterochromaffin cell (EC), then promote neurotransmitters releasing such as 5-HT transmitting to brain, which results in inhibition of sympathetic nervous system activation and lowers blood pressure as well as improves the vascular homeostasis. This project aims to apply spontaneously hypertensive rats in study both in vitro and in vivo. We focus on effects of Roux-en-Y gastric bypass surgery on rat vascular structure and function, activity of sympathetic nervous system, intestinal EC function as well as intestinal absorption and motor function. This study will reveal the role of gastrointestinal TRPA1 in the pathogenesis of hypertension and provides experimental evidence for gastrointestinal intervention for cardiovascular disease.

胃肠道内环境稳态异常是导致心血管代谢病的重要因素，胃肠道干预能有效防治心血管代谢异常，但机制缺乏深入研究。我们前期工作提示胃肠转流术能降低血压及抑制交感活性，但机制不清楚。胃肠粘膜感受器瞬时受体电位锚蛋白1通道（TRPA1）能感受胃肠内环境变化，通过内脏神经将抑制信号传递至血压中枢发挥重要作用。我们发现TRPA1在血管外膜及肠粘膜上均有表达，参与血管外神经对血管功能的调控。为此，我们提出以下理论假设：胃肠转流术可能通过改变胃肠内环境激活肠道TRPA1，促进肠道EC细胞释放5-HT等神经递质，增加交感抑制信号的中枢传入，从而降低交感神经过度激活，导致血压下降和改善血管稳态。本项目拟采用自发性高血压大鼠，在整体与离体水平研究胃肠转流术对大鼠血管结构和功能以及血压、交感神经系统兴奋性、肠道EC细胞数量和功能等作用，阐明胃肠粘膜感受器TRPA1在高血压发病中的机制，为心血管病的胃肠道干预提供依据。

胃肠道内环境稳态异常是导致心血管代谢病的重要因素，胃肠道干预能有效防治心血管代谢异常，但其机制缺乏深入研究。胃肠粘膜感受器瞬时受体电位锚蛋白1通道（TRPA1）能感受胃肠内环境变化，通过内脏神经将抑制信号传递至血压中枢发挥重要作用。我们证实TRPA1主要分布在血管外膜，并参与血管外神经对血管功能的调控。明确了SHR大鼠胃肠转流术后血压和心率显著降低，且胃肠转流术对血管、心脏等靶器官有显著的保护作用。急性冷刺激检测大鼠心率和血压证实胃肠转流术后大鼠心率和血压的变异性显著降低，阐明胃肠转流术能显著抑制交感神经的活性。我们通过人群调查证实，胃肠转流术可以显著改善患者的高血压状态，抑制交感过度激活降低心率，减少高血压患者的用药量及种类。. 阐明胃肠转流术手术能抑制大鼠腹腔外周神经放电活动及降压的机制。胃肠转流术通过改变食物的胃肠通路、增加了转流段肠道管壁压力，激活肠道TRPA1，促进肠道EC细胞释放5-HT等神经递质，增加交感抑制信号的中枢传入，从而降低交感神经过度激活，导致血压下降和改善血管稳态。本项目采用自发性高血压大鼠，在整体与离体水平研究了胃肠转流术对大鼠血管结构和功能以及血压、交感神经系统兴奋性、肠道EC细胞的功能等，阐明胃肠粘膜感受器TRPA1在高血压发病中的机制，为心血管病的胃肠道干预提供依据，尤其对肥胖合并高血压的临床治疗具有启示意义。