论文部分内容阅读
VEGF-A promotes new blood vessel formation during development,and during normal and pathological angiogenesis postnatally.Phosphoinositide-dependent signaling is critical for downstream transmission of cellular responses to VEGF-A.We show that CDP-diacylglycerol synthetase(CDS)is critical for regulation of VEGF-A signaling and angiogenesis.CDS activity maintains PtdIns(4,5)P2(PIP2)availability through re-synthesis of phosphatidylinositides,while VEGFA,mainly through PLCg1,consumes PIP2 for signal transduction.Loss of CDS2,one of two vertebrate CDS enzymes,results in vascular-specific defects in zebrafish in vivo and failure of VEGFA-induced angiogenesis in endothelial cells in vitro.In the absence of CDS2,high level or sustained VEGFA stimulation results in dramatic reduction in PIP2 levels,collapse of VEGFA signaling,and failure of vascular formation.CDS2 deficit-caused phenotypes can be successfully rescued by artificial elevation of PIP2 levels,and excessive PIP2 or increased CDS2 activity can promote excess angiogenesis.Our results indicate that availability of PIP2 is rate-limiting for angiogenesis,and suggest that phosphoinositide recycling may provide a novel target for pro- or anti-angiogenic therapies.