| 1 | Endothelial CDS2 deficiency causes VEGFA-mediated vascular regression and tumor inhibition显示文摘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. | 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 | 2019 | Cell Research2019，29，11： | 9 |
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