VEGF-D/VEGFR-3调控eNOS/NO信号通路在门静脉高压症动脉重构中的作用机制研究

动脉重构是门静脉高压症（PHT）导致的肝外血管重要病理学改变，其对于了解PHT的产生和维持机制有重要意义。前期研究发现，PHT大鼠肠系膜动脉（SMA）内皮细胞（EC）中VEGFR-3和eNOS表达增加，内脏血管发生扩张的同时管壁发生结构性改变，平滑肌细胞（SMC）凋亡增加，血管变薄；且体外实验表明，VEGF-D诱导VEGFR-3激活下游eNOS磷酸化信号通路。据此我们提出假说，在肝硬化PHT的发生发展中，肝外SMA上EC层外源VEGF-D与VEGFR-3信号结合增多，引起下游AKT、ERK磷酸化，eNOS活性上调，NO释放增多，诱导血管SMC发生凋亡，引起肝外SMA重构。本研究拟从分子、细胞和整体水平，利用原代细胞共培养体系、不同的PHT动物模型和PHT病人标本，探讨在动脉重构中VEGFR-3如何调控eNOS/NO信号通路，系统阐述PHT血管重构的产生机制，为PHT病人的诊治提供新的思路。

Arterial remodeling is an important pathological change of extrahepatic vessels caused by portal hypertension (PHT), which is of great significance for mechanism of PHT. Previous studies have shown that the expression of VEGFR-3 and eNOS in the endothelial cells (EC) of the mesenteric artery (SMA) of PHT rats are increased, and the vascular wall is changed with the dilation of visceral blood vessels, and the apoptosis of smooth muscle cells (SMC) is increased and the blood vessels are thinning. Moreover, it showed that VEGF-D induced VEGFR-3 to activate phosphorylation eNOS signaling pathway in vitro experiments. Therefore, we proposed the hypothesis that during the occurrence and development of PHT in liver cirrhosis, the combination of exogenous VEGF-D and VEGFR-3 signals on the EC layer of extrahepatic SMA increased. It induced AKT and ERK phosphorylation, and upregulation of eNOS activity and increased NO released, inducing apoptosis of vascular SMC and causing extrahepatic SMA remodeling. This study aims to explore how VEGFR-3 regulates eNOS/NO signaling pathway in arterial remodeling at the molecular level, cellular and overall level by using primary cell co-culture system, different PHT animal models and PHT patient specimens, and systematically elaborate the generation mechanism of PHT vascular remodeling, thus providing a new idea for the diagnosis and treatment of PHT patients.