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血管内皮生长因子受体3通过β-阿雷斯1调节内皮功能

Zhiyuan Ma¹, Yen-Rei Yu², Cristian T Badea³

¹Division of Cardiology (Z.M., X.X., S.R.), Duke University Medical Center, Durham, NC.

|December 28, 2018

概括

在血管内皮生长因子受体3 (VEGFR3) 信号传递中,β-arrestin (ARRB1) 起着关键作用,影响肺动脉高血压 (PAH). 促进ARRB1功能可以治疗血管疾病.

科学领域:

血管生物学
分子信号
心血管研究

背景情况:

内皮功能依赖于受体信号,在诸如肺动脉高血压 (PAH) 这样的血管疾病中经常出现调节障碍.
血管内皮生长因子受体 (VEGFR) 和G蛋白合受体通常会激活不同的通路,对它们的交叉交谈机制的理解有限.
主要用于调节G蛋白结合受体的β-arrestin (ARRB) 蛋白在其他受体系统和血管疾病中的作用尚不清楚.

研究的目的:

研究β-arrestin1 (ARRB1) 在内皮血管内皮生长因子受体3 (VEGFR3) 信号传递中的作用.
在血管疾病的背景下阐明ARRB1与VEGFR3相互作用及其下游信号的机制.

主要方法:

使用人类PAH样本,人类肺部微血管内皮细胞和Arrb淘汰小鼠.
进行生物化学分析以评估ARRB1- VEGFR3相互作用,下游信号和VEGFR3内部化.
研究ARRB1删除/抑制对内皮细胞功能和PAH发展的影响.

主要成果:

在人类PAH样本中,ARRB1和VEGFR3的表达减少.
在小鼠中,Arrb1删除恶化了低氧诱导的PAH,与VEGFR3信号丧失相关.
降低ARRB1抑制了VEGF- C诱导的内皮细胞增殖,迁移和管形成,减少了VEGFR3,Akt和eNOS酸化.
ARRB1直接与VEGFR3激酶域结合,从而降低了VEGFR3的内部化.

结论:

证明ARRB1在调节VEGFR3信号中的新角色.
在PAH中确定了G蛋白结合受体和VEGFR之间的交叉对话机制.
表明增强ARRB1介导的VEGFR3信号可能是肺高血压和其他血管疾病的治疗策略.

关键词:

GTP结合蛋白质贝塔-阿雷斯高血压,肺部疾病血管内皮生长因子受体

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