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PNAS:血管内皮细胞“Gab1-PKA-eNOS”信号转导通路在缺血性血管新生过程中起关键作用

2011年02月12日 浏览量: 评论(0) 来源:北京大学 作者:佚名 责任编辑:lwc
摘要:血管新生是心脑、肌肉等组织器官缺血缺氧后进行自身修复的重要环节,在促进血液循环、防止组织损伤及改善器官功能等方面起着重要作用。

北京大学分子医学研究所(IMM)罗金才研究组发现,血管内皮细胞“Gab1-PKA-eNOS”信号转导通路在缺血性血管新生过程中起关键作用。


附图:Gab1基因敲除导致小鼠缺血性血管新生、侧枝循环建立出现缺陷(图示上半部分),主要是由于血管内皮细胞管状结构形成的信号调控通路出现障碍而引起的(图示下半部分)。

血管新生是心脑、肌肉等组织器官缺血缺氧后进行自身修复的重要环节,在促进血液循环、防止组织损伤及改善器官功能等方面起着重要作用。然而,目前人们对血管新生的信号调控机制尚不完全理解。罗金才研究组发现,信号接头分子Gab1基因敲除的小鼠在缺血性血管新生和侧枝循环重建等方面都存在严重的缺陷。通过细致分析小鼠血管及其内皮细胞,他们探明Gab1基因敲除导致血管内皮细胞生长因子(VEGF)形成管状结构的信号系统出现障碍(如图所示)。在进一步研究VEGF信号系统时,意外发现Gab1参与调节的并非人们所熟知的Akt-eNOS通路,而是一条尚未见诸报道的PKA-eNOS通路。此外,新发现的“Gab1-PKA-eNOS”信号转导通路对于人的血管内皮细胞形成管状结构也起到不可或缺的作用。罗金才研究组的这一发现为缺血性疾病的防治提供了潜在药物靶点。

该论文由罗金才实验室博士研究生路瑶和熊彦作为共同第一作者,与国内外有关单位合作完成。该研究项目得到了北京大学“985工程”、国家自然科学基金委及国家973项目等科学基金的资助。

原文出处:

PNAS   doi: 10.1073/pnas.1009395108

Grb-2–associated binder 1 (Gab1) regulates postnatal ischemic and VEGF-induced angiogenesis through the protein kinase A–endothelial NOS pathway

Yao Lua,1, Yan Xionga,1, Yingqing Huoa, Jingyan Hanb, Xiao Yangc, Rongli Zhangd, De-Sheng Zhue, Stefan Klein-He?lingf, Jun Lie, Xiaoyu Zhanga, Xiaofan Hana, Yanli Lia, Bin Sheng, Yulong Heg, Masabumi Shibuyah, Gen-Sheng Fengi, and Jincai Luoa,2

Abstract

The intracellular signaling mechanisms underlying postnatal angiogenesis are incompletely understood. Herein we show that Grb-2–associated binder 1 (Gab1) plays a critical role in ischemic and VEGF-induced angiogenesis. Endothelium-specific Gab1 KO (EGKO) mice displayed impaired angiogenesis in the ischemic hindlimb despite normal induction of VEGF expression. Matrigel plugs with VEGF implanted in EGKO mice induced fewer capillaries than those in control mice. The vessels and endothelial cells (ECs) derived from EGKO mice were defective in vascular sprouting and tube formation induced by VEGF. Biochemical analyses revealed a substantial reduction of endothelial NOS (eNOS) activation in Gab1-deficient vessels and ECs following VEGF stimulation. Interestingly, the phosphorylation of Akt, an enzyme known to promote VEGF-induced eNOS activation, was increased in Gab1-deficient vessels and ECs whereas protein kinase A (PKA) activity was significantly decreased. Introduction of an active form of PKA rescued VEGF-induced eNOS activation and tube formation in EGKO ECs. Reexpression of WT or mutant Gab1 molecules in EGKO ECs revealed requirement of Gab1/Shp2 association for the activation of PKA and eNOS. Taken together, these results identify Gab1 as a critical upstream signaling component in VEGF-induced eNOS activation and tube formation, which is dependent on PKA. Of note, this pathway is conserved in primary human ECs for VEGF-induced eNOS activation and tube formation, suggesting considerable potential in treatment of human ischemic diseases.

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