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

  1. Weijun Pan1,*,
  2. Van N. Pham1,*,
  3. Amber N. Stratman2,
  4. Daniel Castranova1,
  5. Makoto Kamei1,,
  6. Kameha R. Kidd1,,
  7. Brigid D. Lo1,,
  8. Kenna M. Shaw1,,
  9. Jesus Torres-Vazquez1,,
  10. Constantinos M. Mikelis3,
  11. J. Silvio Gutkind3,
  12. George E. Davis2, and
  13. Brant M. Weinstein1
  1. 1Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD;
  2. 2Department of Medical Pharmacology and Physiology, School of Medicine, Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, MO; and
  3. 3Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD

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.

  • Submitted February 1, 2012.
  • Accepted May 12, 2012.
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