PUBLICATION

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
Abstract

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.

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Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes