TY - JOUR
T1 - CDP-diacylglycerol synthetase-controlled phosphoinositide availability limits VEGFA signaling and vascular morphogenesis
AU - Pan, Weijun
AU - Van Pham, N.
AU - Stratman, Amber N.
AU - Castranova, Daniel
AU - Kamei, Makoto
AU - Kidd, Kameha R.
AU - Lo, Brigid D.
AU - Shaw, Kenna M.
AU - Torres-Vazquez, Jesus
AU - Mikelis, Constantinos M.
AU - Silvio Gutkind, J.
AU - Davis, George E.
AU - Weinstein, Brant M.
PY - 2012/7/12
Y1 - 2012/7/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84864071567&partnerID=8YFLogxK
U2 - 10.1182/blood-2012-02-408328
DO - 10.1182/blood-2012-02-408328
M3 - Article
C2 - 22649102
AN - SCOPUS:84864071567
VL - 120
SP - 489
EP - 498
JO - Blood
JF - Blood
SN - 0006-4971
IS - 2
ER -