Lysophosphatidic acid suppresses endothelial cell CD36 expression and promotes angiogenesis via a PKD-1-dependent signaling pathway. Blood 2011 Jun 02;117(22):6036-45
Date
03/29/2011Pubmed ID
21441463Pubmed Central ID
PMC3112047DOI
10.1182/blood-2010-12-326017Scopus ID
2-s2.0-79957982626 (requires institutional sign-in at Scopus site) 43 CitationsAbstract
In pathologic settings including retinal ischemia and malignant tumors, robust angiogenesis occurs despite the presence in the microenvironment of antiangiogenic proteins containing thrombospondin structural homology (TSR) domains. We hypothesized that antiangiogenesis mediated by TSR-containing proteins could be blunted by localized down-regulation of their cognate receptor on microvascular endothelial cells (MVECs), CD36. Through screening a panel of endothelial cell agonists, we found that lysophosphatidic acid (LPA) dramatically down-regulated CD36 surface expression on primary MVECs. LPA is a lipid-signaling mediator known to have proangiogenic activity, but the mechanisms are largely unknown. We observed that LPA caused CD36 down-regulation in a dose- and time-dependent manner and was long lasting. Down-regulation occurred at the transcriptional level via a signaling pathway involving specific LPA receptors and protein kinase D. LPA-induced MVEC CD36 repression significantly attenuated in vitro antiangiogenic responses to thrombospondin-1, including blockade of migration, tube formation, and VEGFR-2 signaling in response to fibroblast growth factor-2. In vivo relevance was demonstrated by showing that LPA abrogated thrombospondin-1-mediated inhibition of neovascularization of Matrigel plugs implanted in mice. Our data thus indicate that the proangiogenic mechanism of LPA may in part be via switching off the antiangiogenic switch mediated by TSR proteins and CD36.
Author List
Ren B, Hale J, Srikanthan S, Silverstein RLAuthor
Roy L. Silverstein MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBlotting, Western
CD36 Antigens
Cell Adhesion
Cell Movement
Cell Proliferation
Cells, Cultured
Dermis
Down-Regulation
Endothelium, Vascular
Humans
Immunoenzyme Techniques
Immunoprecipitation
Lysophospholipids
Mice
Neovascularization, Physiologic
RNA, Messenger
RNA, Small Interfering
Receptors, Lysophosphatidic Acid
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
TRPP Cation Channels
Thrombospondin 1
Transcription, Genetic
