Thrombospondins 1 and 2 Function As Inhibitors of Angiogenesis

Thrombospondins (TSPs) 1 and 2 are matricellular proteins with the well-characterized ability to inhibit angiogenesis in vivo, and the migration and proliferation of cultured microvascular endothelial cells (ECs). Angiogenesis in developing tumors and in various models of wound healing is diminished or delayed by the presence of TSP1 or 2. Sequences within the type I repeats of TSP1 and 2 have been demonstrated to mediate the anti-migratory effects of TSPs on microvascular EC, although, paradoxically, sequences in the N- and C-terminal domains have pro-angiogenic effects. A scavenger receptor, CD36, recognizes the active sequences in the type I repeats, and is required for the anti-angiogenic effects of TSP1 in the corneal neovascularization assay. However, interactions of TSPs with growth factors, proteases, histidine-rich glycoprotein, and other cell-surface receptors on EC have the potential to modulate CD36-mediated effects. Binding of TSP1 to CD36 has been shown to activate apoptosis by inducing p38 and Jun N-terminal kinase, members of the mitogen-activated protein kinase superfamily, and subsequently the cell-surface expression of FasL. Ligation of Fas by FasL then induces a caspase cascade and apoptotic cell death. However, we have recently shown that inhibition of proliferation of microvascular EC by TSPs can occur in the absence of cell death. This finding raises the possibility that TSPs can activate separate cell death and anti-proliferative pathways.