Phospholipase Cγ Activation Drives Increased Production of Autotaxin in Endothelial Cells and Lysophosphatidic Acid-Dependent Regression

Abstract

We previously reported that vascular endothelial growth factor (VEGF)-dependent activation of phospholipase Cγ1 (PLCγ) regulated tube stability by competing with phosphoinositide 3-kinase (PI3K) for their common substrate. Here we describe an additional mechanism by which PLCγ promoted regression of tubes and blood vessels. Namely, it increased the level of autotaxin (ATX), which is a secreted form of lysophospholipase D that produces lysophosphatidic acid (LPA). LPA promoted motility of endothelial cells, leading to disorganization/regression of tubes in vitro. Furthermore, mice that under- or overexpressed members of this intrinsic destabilization pathway showed either delayed or accelerated, respectively, regression of blood vessels. We conclude that endothelial cells can be instructed to engage a PLCγ-dependent intrinsic destabilization pathway that results in the production of soluble regression factors such as ATX and LPA. These findings are likely to potentiate ongoing efforts to prevent, manage, and eradicate numerous angiogenesis-based diseases such as proliferative diabetic retinopathy and solid tumors.

We are very grateful to Susan Pyne (Strathcylde Institute of Pharmacy and Biomedical Science, Glasgow, United Kingdom) for the LPP1 construct and to Demin Wang and James Schuman for providing the PLCγ^+/+ and PLCγ^+/− mice.

This study was supported by a Young Clinical Scientist Award from the Flight Attendant Medical Research Institute (to E.I.), NIH/NIDDK grant 1KO1 DK083336 (to E.I.), NIH grant EY016385 (to A.K.), and Pew Latin American Fellows Program in the Biomedical Sciences and American Diabetes Association Mentor-Based Minority Postdoctoral Fellowship 7-09-MI-04 (to J.A.). This research was also supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and Center for Cancer Research (to T.C. and M.S.).