Phospholipase Cgamma activation drives increased production of autotaxin in endothelial cells and lysophosphatidic acid-dependent regression.
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.
Im
Eunok
E
Schepens Eye Research Institute, Harvard Medical School, 20 Staniford St., Boston, MA 02114, USA.
Motiejunaite
Ruta
R
Aranda
Jorge
J
Park
Eun Young
EY
Federico
Lorenzo
L
Kim
Tae-im
TI
Clair
Timothy
T
Stracke
Mary L
ML
Smyth
Susan
S
Kazlauskas
Andrius
A
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D004789:Enzyme Activation; D005123:Eye / Q000098:blood supply; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D043264:Phosphodiesterase I / Q000235:genetics / Q000378:metabolism*; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099189:Lysophospholipase D
D019703:Calcineurin; D008246:Lysophospholipids; D009097:Multienzyme Complexes; D019869:Phosphatidylinositol 3-Kinases; D043264:Phosphodiesterase I; D051966:Phospholipase C gamma; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid