血管生成素-1通过mDia隔离Src来防止VEGF诱导的内皮细胞通透性增加。

Angiopoietin-1 prevents VEGF-induced endothelial permeability by sequestering Src through mDia.

作者信息

Gavard Julie, Patel Vyomesh, Gutkind J Silvio

机构信息

Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892-4340, USA.

出版信息

Dev Cell. 2008 Jan;14(1):25-36. doi: 10.1016/j.devcel.2007.10.019.

DOI:10.1016/j.devcel.2007.10.019

PMID:18194650

Abstract

Vascular endothelial growth factor (VEGF) and Angiopoietin 1 (Ang1) are both potent proangiogenic factors, but, whereas VEGF causes vascular permeability, Ang1 stabilizes blood vessels and protects them from VEGF-induced plasma leakage. The antivascular permeability mechanisms deployed by Ang1 are still undefined. Here, we demonstrate that Ang1 halts the ability of VEGF to induce the phosphorylation-dependent redistribution of the adhesion molecule VE-cadherin, thereby rescuing the endothelial barrier function. Ang1 inhibits the activation of Src by VEGF, the most upstream component of the pathway linking VEGF receptors to VE-cadherin internalization. Indeed, Ang1 promotes the activation of mDia through RhoA, resulting in the association of mDia with Src. This ultimately deprives VEGF receptors of an essential molecule required for promoting the disruption of endothelial cell-cell contacts and paracellular permeability.

摘要

血管内皮生长因子（VEGF）和血管生成素1（Ang1）都是强效的促血管生成因子，然而，VEGF会导致血管通透性增加，而Ang1则可稳定血管并保护其免受VEGF诱导的血浆渗漏。Ang1所采用的抗血管通透性机制仍不明确。在此，我们证明Ang1可阻止VEGF诱导黏附分子VE-钙黏蛋白发生磷酸化依赖性重新分布的能力，从而挽救内皮屏障功能。Ang1可抑制VEGF对Src的激活，Src是将VEGF受体与VE-钙黏蛋白内化相联系的信号通路中最上游的成分。实际上，Ang1通过RhoA促进mDia的激活，导致mDia与Src结合。这最终使VEGF受体失去了促进内皮细胞间接触破坏和细胞旁通透性所需的关键分子。