Phospholipase Cgamma activation drives increased production of autotaxin in endothelial cells and lysophosphatidic acid-dependent regression

Mol Cell Biol. 2010 May;30(10):2401-10. doi: 10.1128/MCB.01275-09. Epub 2010 Mar 15.


We previously reported that vascular endothelial growth factor (VEGF)-dependent activation of phospholipase Cgamma1 (PLCgamma) regulated tube stability by competing with phosphoinositide 3-kinase (PI3K) for their common substrate. Here we describe an additional mechanism by which PLCgamma 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 PLCgamma-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcineurin / metabolism
  • Cattle
  • Cells, Cultured
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism*
  • Enzyme Activation
  • Eye / blood supply
  • Humans
  • Lysophospholipids* / metabolism
  • Lysophospholipids* / pharmacology
  • Mice
  • Mice, Transgenic
  • Multienzyme Complexes / genetics
  • Multienzyme Complexes / metabolism*
  • Neovascularization, Physiologic / physiology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphodiesterase I / genetics
  • Phosphodiesterase I / metabolism*
  • Phospholipase C gamma / genetics
  • Phospholipase C gamma / metabolism*
  • Phosphoric Diester Hydrolases
  • Pyrophosphatases / genetics
  • Pyrophosphatases / metabolism*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Vascular Endothelial Growth Factor A / metabolism


  • Lysophospholipids
  • Multienzyme Complexes
  • RNA, Small Interfering
  • Vascular Endothelial Growth Factor A
  • Phosphatidylinositol 3-Kinases
  • Calcineurin
  • Phosphoric Diester Hydrolases
  • Phosphodiesterase I
  • Phospholipase C gamma
  • alkylglycerophosphoethanolamine phosphodiesterase
  • Pyrophosphatases
  • lysophosphatidic acid