CDP-diacylglycerol synthetase-controlled phosphoinositide availability limits VEGFA signaling and vascular morphogenesis.
Understanding the mechanisms that regulate angiogenesis and translating these into effective therapies are of enormous scientific and clinical interests. In this report, we demonstrate the central role of CDP-diacylglycerol synthetase (CDS) in the regulation of VEGFA signaling and angiogenesis. CDS activity maintains phosphoinositide 4,5 bisphosphate (PIP2) availability through resynthesis of phosphoinositides, whereas VEGFA, mainly through phospholipase Cγ1, consumes PIP2 for signal transduction. Loss of CDS2, 1 of 2 vertebrate CDS enzymes, results in vascular-specific defects in zebrafish in vivo and failure of VEGFA-induced angiogenesis in endothelial cells in vitro. Absence of CDS2 also results in reduced arterial differentiation and reduced angiogenic signaling. CDS2 deficit-caused phenotypes can be successfully rescued by artificial elevation of PIP2 levels, and excess PIP2 or increased CDS2 activity can promote excess angiogenesis. These results suggest that availability of CDS-controlled resynthesis of phosphoinositides is essential for angiogenesis.
Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
Weijun
W
Pan
Van N
VN
Pham
Amber N
AN
Stratman
Daniel
D
Castranova
Makoto
M
Kamei
Kameha R
KR
Kidd
Brigid D
BD
Lo
Kenna M
KM
Shaw
Jesus
J
Torres-Vazquez
Constantinos M
CM
Mikelis
J Silvio
JS
Gutkind
George E
GE
Davis
Brant M
BM
Weinstein
D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D001808:Blood Vessels / Q000196:embryology / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D002798:Diacylglycerol Cholinephosphotransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D018919:Neovascularization, Physiologic / Q000235:genetics; D010716:Phosphatidylinositols / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D018076:DNA, Complementary; D010716:Phosphatidylinositols; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D029961:Zebrafish Proteins; D002798:Diacylglycerol Cholinephosphotransferase