CDP-diacylglycerol synthetase-controlled phosphoinositide availability limits VEGFA signaling and vascular morphogenesis
- Authors
- Pan, W., Pham, V.N., Stratman, A.N., Castranova, D., Kamei, M., Kidd, K.R., Lo, B.D., Shaw, K.M., Torres-Vazquez, J., Mikelis, C.M., Gutkind, J.S., Davis, G.E., and Weinstein, B.M.
- ID
- ZDB-PUB-120601-4
- Date
- 2012
- Source
- Blood 120(2): 489-498 (Journal)
- Registered Authors
- Castranova, Dan, Kamei, Makoto, Kidd, Kameha, Lo, Brigid, Pham, Van, Torres-Vazquez, Jesus, Weinstein, Brant M.
- Keywords
- none
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Base Sequence
- Blood Vessels/embryology
- Blood Vessels/metabolism
- DNA, Complementary/genetics
- Diacylglycerol Cholinephosphotransferase/genetics
- Diacylglycerol Cholinephosphotransferase/metabolism*
- Humans
- Mutation
- Neovascularization, Physiologic/genetics
- Phosphatidylinositols/metabolism*
- RNA, Small Interfering/genetics
- Signal Transduction
- Vascular Endothelial Growth Factor A/metabolism*
- Zebrafish/embryology*
- Zebrafish/genetics
- Zebrafish/metabolism*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 22649102 Full text @ Blood
Understanding the mechanisms regulating angiogenesis and translating these into effective therapies is of enormous scientific and clinical interest. In this report, we demonstrate the central role of CDP-diacylglycerol synthetase (CDS) in the regulation of VEGFA signaling and angiogenesis. CDS activity maintains PtdIns (4,5)P2 (PIP2) availability through re-synthesis of phosphoinositides, 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. 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 demonstrate that availability of CDS-controlled re-synthesis of phosphoinositides is essential for angiogenesis.