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.