学科主题基础医学
Grb-2-associated binder 1 (Gab1) regulates postnatal ischemic and VEGF-induced angiogenesis through the protein kinase A-endothelial NOS pathway
Lu, Yao1; Xiong, Yan1; Huo, Yingqing1; Han, Jingyan2; Yang, Xiao3; Zhang, Rongli4; Zhu, De-Sheng5; Klein-Hessling, Stefan6; Li, Jun5; Zhang, Xiaoyu1; Han, Xiaofan1; Li, Yanli1; Sheng, Bin7; He, Yulong7; Shibuya, Masabumi8; Feng, Gen-Sheng9; Luo, Jincai1
关键词NO Gab1 protein complex collateralization Tie2-Cre PKA substrate
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2011-02-15
DOI10.1073/pnas.1009395108
108期:7页:2957-2962
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Multidisciplinary Sciences
研究领域[WOS]Science & Technology - Other Topics
关键词[WOS]NITRIC-OXIDE SYNTHASE ; GROWTH-FACTOR ; SIGNAL-TRANSDUCTION ; IN-VIVO ; ARTERIOGENESIS ; ACTIVATION ; RECEPTOR-2 ; MIGRATION ; AKT1 ; CELL
英文摘要

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.

语种英语
WOS记录号WOS:000287377000062
项目编号30671030 ; 90607004 ; 2007CB512100 ; 2009ZX09501-027 ; Transregio TR52 ; 17014020 ; R01HL096125
资助机构National Science Fund ; Major State Basic Program of China ; Key Project for Drug Discovery and Development in China ; German Research Foundation ; Ministry of Education, Culture, Sports, Science and Technology of Japan ; National Institutes of Health Research
引用统计
被引频次:43[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/62603
专题北京大学基础医学院_北大医学部天士力微循环研究中心
北京大学第一临床医学院_病理科
北京大学第三临床医学院_医学工程处
北京大学口腔医学院_中心实验室
作者单位1.Peking Univ, Anim Ctr, Beijing 100871, Peoples R China
2.Inst Biotechnol, Genet Lab Dev & Dis, Beijing 100071, Peoples R China
3.Peking Univ, Inst Mol Med, Lab Vasc Biol, Beijing 100871, Peoples R China
4.Peking Univ, Tasly Microcirculat Res Ctr, Sch Basic Med Sci, Dept Integrat Chinese & Western Med, Beijing 100871, Peoples R China
5.Peking Univ, Inst Mol Med, Non Human Primate Ctr, Beijing 100871, Peoples R China
6.Univ Wurzburg, Inst Pathol, Dept Mol Pathol, D-97080 Wurzburg, Germany
7.Nanjing Univ, Model Anim Res Inst, Lab Vasc & Canc Biol, Nanjing 210061, Peoples R China
8.Tokyo Med & Dent Univ, Dept Mol Oncol, Tokyo 1138510, Japan
9.Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92093 USA
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GB/T 7714
Lu, Yao,Xiong, Yan,Huo, Yingqing,et al. Grb-2-associated binder 1 (Gab1) regulates postnatal ischemic and VEGF-induced angiogenesis through the protein kinase A-endothelial NOS pathway[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2011,108(7):2957-2962.
APA Lu, Yao.,Xiong, Yan.,Huo, Yingqing.,Han, Jingyan.,Yang, Xiao.,...&Luo, Jincai.(2011).Grb-2-associated binder 1 (Gab1) regulates postnatal ischemic and VEGF-induced angiogenesis through the protein kinase A-endothelial NOS pathway.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,108(7),2957-2962.
MLA Lu, Yao,et al."Grb-2-associated binder 1 (Gab1) regulates postnatal ischemic and VEGF-induced angiogenesis through the protein kinase A-endothelial NOS pathway".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 108.7(2011):2957-2962.
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