1. CDP-diacylglycerol synthetase-controlled phosphoinositide availability limits VEGFA signaling and vascular morphogenesis
- Author
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J. Silvio Gutkind, Amber N. Stratman, Brigid D. Lo, Brant M. Weinstein, Constantinos M. Mikelis, Kameha R. Kidd, Makoto Kamei, Weijun Pan, George E. Davis, Kenna M. Shaw, Daniel Castranova, Van N. Pham, Jesús Torres-Vázquez, Pan, Weijun, Pham, Van N, Stratman, Amber N, Castranova, Daniel, Kamei, Makoto, Kidd, Kameha R, Lo, Brigid D, Shaw, Kenna M, Torres-Vázquez, Jesús, Mikelis, Constantinos M, Silvio Gutkind, J, Davis, George E, and Weinstein, Brant M
- Subjects
Vascular Endothelial Growth Factor A ,DNA, Complementary ,Angiogenesis ,Immunology ,Morphogenesis ,Neovascularization, Physiologic ,Phospholipase ,Biology ,Phosphatidylinositols ,Biochemistry ,Animals, Genetically Modified ,Neovascularization ,Vascular Biology ,In vivo ,medicine ,Animals ,Humans ,RNA, Small Interfering ,Zebrafish ,in-vivo ,transgenic zebrafish ,vessel formation ,growth-factor ,angiogenesis ,synthase ,kinase ,vasculogenesis ,Base Sequence ,endothelial lumen formation ,Cell Biology ,Hematology ,Zebrafish Proteins ,biology.organism_classification ,Cell biology ,Vascular endothelial growth factor A ,Diacylglycerol Cholinephosphotransferase ,Mutation ,zebrafish embryos ,Blood Vessels ,lipids (amino acids, peptides, and proteins) ,Signal transduction ,medicine.symptom ,Signal Transduction - Abstract
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.
- Published
- 2012