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

Friday, November 08, 2013 — Poster Session IV
2:00 p.m. – 4:00 p.m.	FAES Academic Center (Upper-Level Terrace)	NICHD	DEVBIO-10

Authors

A.N. Stratman
W Pan
V.N. Pham
C.M. Mikelis
J.S. Gutkind
G.E. Davis
B.M Weinstein

Abstract

Here, we demonstrate a role for CDP-diacylglycerol synthetase (CDS) in the regulation of VEGFA induced angiogenesis during zebrafish vascular development. CDS activity is required for the maintenance of PtdIns-(4,5)P2-(PIP2) availability, a known molecule consumed by the VEGFA signalling pathway. Loss of CDS2 results in vascular-specific defects in the zebrafish, including inhibited angiogenic sprouting of the trunk intersegmental vessels (ISV) and loss of central artery sprouting in the brain. Further, absence of CDS2 results in reduced expression of arterial differentiation markers. The CDS deficient vascular phenotypes can be rescued by supplying exogenous PIP2 into the system, circumventing the need for CDS-controlled re-synthesis of phosphoinositides and restoring ISV formation back to control conditions. Additionally, loss of CDS activity leads to a reduction in Erk, Akt and N-Fat activation downstream of VEGFA stimulation. Interestingly, in CDS2 mutants specifically, exogenous overexpression of active VEGFA exacerbates the vascular phenotypes, presumably through accelerated depletion of PIP2 levels, leading to complete inhibition of angiogenic sprouting, a phenomenon we are currently following up on. Together, these results demonstrate the essential nature of CDS regulated phosphoinositide synthesis in the control of angiogenic sprouting and suggests that further consideration of CDS2 as a therapeutic target may prove useful.