CDP-diacylglycerol synthetase-controlled phosphoinositide availability limits VEGFA signaling and vascular morphogenesis

Weijun Pan, N. Van Pham, Amber N. Stratman, Daniel Castranova, Makoto Kamei, Kameha R. Kidd, Brigid D. Lo, Kenna M. Shaw, Jesus Torres-Vazquez, Constantinos M. Mikelis, J. Silvio Gutkind, George E. Davis, Brant M. Weinstein

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)489-498
Number of pages10
JournalBlood
Volume120
Issue number2
DOIs
Publication statusPublished - 12 Jul 2012

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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