The response of endothelial cells t

The response of endothelial cells to signaling stimulation is critical for vascular morphogenesis, homeostasis and function. Vascularendothelial 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-diacylglycerolsynthetase-2 (CDS2), a metabolic enzyme that controls phosphoinositide recycling, switches the output of VEGFA signaling frompromoting angiogenesis to unexpectedly inducing vessel regression. Live imaging analysis uncovered the presence of reversemigration of the angiogenic endothelium in cds2 mutant zebrafish upon VEGFA stimulation, and endothelium regression alsooccurred 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 tumorgrowth. Mechanistically, VEGFA stimulation reduced phosphatidylinositol (4,5)-bisphosphate (PIP2) availability in the absence ofCDS2-controlled-phosphoinositide metabolism, subsequently causing phosphatidylinositol (3,4,5)-triphosphate (PIP3) deficiencyand FOXO1 activation to trigger regression of CDS2-null endothelium. Thus, our data indicate that the effect of VEGFA onvasculature is context-dependent and can be converted from angiogenesis to vascular regression.