Endothelial CDS2 deficiency causes VEGFA-mediated vascular regression and tumor inhibition  

作　　者：Wencao Zhao Le Cao Hanru Ying Wenjuan Zhang Dantong Li Xiaolong Ziiu Wenzhi Xue Shuang Wu Mengye Cao Cong Fu Haonan Qi Yimei Hao Yun-Chi Tang Jun Qin Tao PZhong Xiaoxi Lin Luyang Yu Xuri Li Lin Li Dianqing Wu Weijun Pan 

机构地区：[1]Key Laboratory of Tissue Microenvironmentand Tumor,CAS Center for Excellencein Molecular Cell Science,Shanghai Institute of Nutrition and Health,University of Chinese Academy of Sciences,Chinese Academy of Sciences(CAS),Shanghai,China [2]Department of Plastic and Reconstructive Surgery,Shanghai Ninth People's Hospital,ShanghaiJiaotong University,School of Medicine,Shanghai,China [3]Shanghai Key Laboratory of Regulatory Biology,Institute of Molecular Medicine,East China Normal University School ofLifeSciences,Shanghai,China [4]Innovative Research Team of High-level Local University in Shanghai,Shanghai,China [5]Institute of Genetics,College of Life Sciences,ZhejiangUniversity,Hangzhou,China [6]State Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangzhou,China [7]State Key Laboratory of Molecular Biology,CAS Center for Excellencein Molecular Cell Science,Institute of Biochemistry and Cell Biology,Shanghai Institutes for Biological Sciences,CAS,Shanghai,China [8]Department of Pharmacology,Vascular Biology and Therapeutic Program,School of Medicine,Yale University,New Haven,CT,USA

出　　处：《Cell Research》2019年第11期895-910,共16页细胞研究（英文版）

基　　金：This work was supported by Ministry of Science and Technology of China(2018YFA0800200 and 2017YF0503600);National Natural Science Foundation of China(31571505 and 31371461),CAS Strategic Priority Research Program(XDB19030000);Scientific Research Equipment Development Project(YZ201646)to WJP.

摘　　要：The response of endothelial cells to signaling stimulation is critical for vascular morphogenesis,homeostasis and function.Vascular endothelial growth factor-a(VEGFA)has been commonly recognized as a pro-angiogenic factor in vertebrate developmental,physiological and pathological conditions for decades.Here we report a novel finding that genetic ablation of CDP-diacylglycerol synthetase-2(CDS2),a metabolic enzyme that controls phosphoinositide recycling,switches the output of VEGFA signaling from promoting angiogenesis to unexpectedly inducing vessel regression.Live imaging analysis uncovered the presence of reverse migration of the angiogenic endothelium in cds2 mutant zebrafish upon VEGFA stimulation,and endothelium regression also occurred in postnatal retina and implanted tumor models in mice.In tumor models,CDS2 deficiency enhanced the level of tumorsecreted VEGFA,which in-turn trapped tumors into a VEGFA-induced vessel regression situation,leading to suppression of tumor growth.Mechanistically,VEGFA stimulation reduced phosphatidylinositol(4,5)-bisphosphate(PIP2)availability in the absence of CDS2-controlled-phosphoinositide metabolism,subsequently causing phosphatidylinositol(3,4,5)-triphosphate(PIP3)deficiency and F0X01 activation to trigger regression of CDS2-null endothelium.Thus,our data indicate that the effect of VEGFA on vasculature is context-dependent and can be converted from angiogenesis to vascular regression.

关 键 词：STIMULATION VEGFA metabolism 

分 类 号：R73[医药卫生—肿瘤]