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

• DOI: 10.1073/pnas.1009395108
• Publication Date: 2011-02-01T04:07:07Z
• Authors: Yao Lu; Yan Xiong; Yingqing Huo; Jingyan Han; Xiao Yang; Rongli Zhang; De-Sheng Zhu; Stefan Klein-Heßling; Jun Li; Xiaoyu Zhang; Xiaofan Han; Yanli Li; Bin Shen; Yulong He; Masabumi Shibuya; Gen-Sheng Feng; Jincai Luo
• Keywords: Matrigel

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 the hindlimb despite normal induction of VEGF expression. Matrigel plugs with implanted EGKO induced fewer capillaries than those control mice. vessels endothelial cells (ECs) derived from were defective vascular sprouting tube formation by VEGF. Biochemical analyses revealed substantial reduction NOS (eNOS) activation Gab1-deficient ECs following stimulation. Interestingly, phosphorylation Akt, an enzyme known to promote eNOS activation, was increased whereas protein kinase A (PKA) activity significantly decreased. Introduction active form PKA rescued ECs. Reexpression WT or mutant molecules requirement Gab1/Shp2 association for eNOS. Taken together, these results identify as upstream component formation, which is dependent on PKA. Of note, this pathway conserved primary human suggesting considerable potential treatment diseases.