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学科主题: 基础医学
题名:
Grb-2-associated binder 1 (Gab1) regulates postnatal ischemic and VEGF-induced angiogenesis through the protein kinase A-endothelial NOS pathway
作者: 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
发表日期: 2011-02-15
DOI: 10.1073/pnas.1009395108
卷: 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
所属项目编号: 30671030 ; 90607004 ; 2007CB512100 ; 2009ZX09501-027 ; Transregio TR52 ; 17014020 ; R01HL096125
项目资助者: 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
WOS记录号: WOS:000287377000062
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/62603
Appears in Collections:基础医学院_北大医学部天士力微循环研究中心_期刊论文

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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

Recommended Citation:
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.
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