title: CD36-TSP-HRGP interactions in the regulation of angiogenesis.
abstract: Thrombospondin (TSP)-1 and -2 are potent inhibitors of angiogenesis in vivo and of microvascular endothelial cell responses to angiogenic factors in vitro. The anti-angiogenic activity of thrombospondins is contained in a structural domain known as the TSP type I repeat or TSR. TSR domains are present in many other proteins, several of which have also been shown to have anti-angiogenic activity and a peptide-mimetic drug based on the domain is in clinical trials as an anti-angiogenic anti-cancer therapy. We have identified CD36 as the endothelial cell receptor for TSP-1 and -2 and showed that it is necessary for their anti-angiogenic activity. CD36-mediated anti-angiogenic activity in endothelial cells is due to its ability to activate a specific signaling cascade that results in diversion of a pro-angiogenic response to an apoptotic response. Recently we identified a circulating protein, histidine-rich glycoprotein (HRGP), that contains a CD36 homology domain and that acts as a soluble decoy to block the anti-angiogenic activities of TSPs, thereby promoting angiogenesis. The tripartite interactions among CD36, TSR domains and HRGP in tissues may play an important role in regulating physiological and pathological angiogenesis.
authors.affiliation: Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. silverr2@ccf.org
authors.forename: Roy L
authors.initials: RL
authors.lastname: Silverstein
authors.forename: Maria
authors.initials: M
authors.lastname: Febbraio
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D018955:CD36 Antigens / Q000737:chemistry / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000737:chemistry / Q000378:metabolism*; D019699:Thrombospondins / Q000737:chemistry / Q000378:metabolism*; D000099053:Histidine-Rich Glycoprotein; D000099262:Thrombospondin 2
chemical_list: D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D018955:CD36 Antigens; D011506:Proteins; D019700:Thrombospondin 1; D019699:Thrombospondins; D000099053:Histidine-Rich Glycoprotein; D000099262:Thrombospondin 2