附圖：Gab1基因敲除導(dǎo)致小鼠缺血性血管新生、側(cè)枝循環(huán)建立出現(xiàn)缺陷（圖示上半部分），主要是由于血管內(nèi)皮細(xì)胞管狀結(jié)構(gòu)形成的信號調(diào)控通路出現(xiàn)障礙而引起的（圖示下半部分）。
血管新生是心腦、肌肉等組織器官缺血缺氧后進(jìn)行自身修復(fù)的重要環(huán)節(jié)，在促進(jìn)血液循環(huán)、防止組織損傷及改善器官功能等方面起著重要作用,。然而，目前人們對血管新生的信號調(diào)控機(jī)制尚不完全理解,。羅金才研究組發(fā)現(xiàn),，信號接頭分子Gab1基因敲除的小鼠在缺血性血管新生和側(cè)枝循環(huán)重建等方面都存在嚴(yán)重的缺陷。通過細(xì)致分析小鼠血管及其內(nèi)皮細(xì)胞,，他們探明Gab1基因敲除導(dǎo)致血管內(nèi)皮細(xì)胞生長因子（VEGF）形成管狀結(jié)構(gòu)的信號系統(tǒng)出現(xiàn)障礙（如圖所示）,。在進(jìn)一步研究VEGF信號系統(tǒng)時,意外發(fā)現(xiàn)Gab1參與調(diào)節(jié)的并非人們所熟知的Akt-eNOS通路，而是一條尚未見諸報道的PKA-eNOS通路,。此外,，新發(fā)現(xiàn)的“Gab1-PKA-eNOS”信號轉(zhuǎn)導(dǎo)通路對于人的血管內(nèi)皮細(xì)胞形成管狀結(jié)構(gòu)也起到不可或缺的作用。羅金才研究組的這一發(fā)現(xiàn)為缺血性疾病的防治提供了潛在藥物靶點(diǎn),。
該論文由羅金才實(shí)驗(yàn)室博士研究生路瑤和熊彥作為共同第一作者,，與國內(nèi)外有關(guān)單位合作完成。該研究項(xiàng)目得到了北京大學(xué)“985工程”,、國家自然科學(xué)基金委及國家973項(xiàng)目等科學(xué)基金的資助,。（生物谷Bioon.com）
生物谷推薦原文出處：
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.
