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Thrombospondin‐1, PECAM‐1, and Regulation of Angiogenesis
Author(s) -
Sheibani Nader
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a21-d
Subject(s) - angiogenesis , thrombospondin 1 , neovascularization , microbiology and biotechnology , biology , thrombospondin , mapk/erk pathway , cancer research , retinal , angiostatin , signal transduction , genetics , matrix metalloproteinase , biochemistry , metalloproteinase
Negative regulators of angiogenesis play a central role in keeping angiogenesis in check. Expression of thrombospondin‐1 (TSP1), an endogenous inhibitor of angiogenesis, is down‐regulated during the progression of many tumors and diabetes favoring a proangiogenic state. We have shown TSP1 expression in the endothelial cells (EC) promotes a quiescent, differentiated phenotype through regulation of a number of genes with important roles in angiogenesis. One such gene is PECAM‐1, a proangiogenic molecule whose expression is down‐regulated upon TSP1 expression in EC. We also showed down‐regulation of PECAM‐1 expression in EC results in increased expression of TSP1. Therefore, TSP1 and PECAM‐1 are constituents of a regulatory switch whose reciprocal regulation, perhaps through the MAPK/ERKs pathway, promotes or inhibits angiogenesis. Our recent in vivo studies indicate TSP1 expression is essential for normal development of retinal vasculature and regression of embryonic and newly formed vessels during oxygen‐induced ischemic retinopathy. Most recently, we have shown retinal endothelium continues to express proangiogenic isoforms of PECAM‐1 at higher frequencies in the absence of TSP1. We have also found PECAM‐1 is essential for normal retinal vascularization and neovascularization during oxygen‐induced ischemic retinopathy. These studies demonstrate the important physiological roles of TSP1 and PECAM‐1 in vascular development and neovascularization. Furthermore, TSP1 or PECAM‐1 deficient EC maintain many of their respective in vivo characteristics in culture. Utilization of these EC and study of their adhesive and migratory properties upon restoration of TSP1 or a specific PECAM‐1 isoform will provide additional insight into the cellular mechanisms utilized by these molecules to regulate EC phenotype.