36 - Thrombospondins

Summary

The thrombospondins (TSPs) are a family of proteins that regulate cellular phenotype and matrix structure during tissue remodeling and genesis (1,2). Of the five proteins that comprise the family, TSP-1 and -2 have been shown to be involved in vascular development and angiogenesis (3,4). The endothelial cell (EC) integrates positive and negative signals for proliferation, migration, survival, and apoptosis during physiological and pathological angiogenesis. TSP-1 and -2 suppress the angiogenic response by inhibiting migration and antagonizing vascular endothelial growth factor (VEGF)-induced survival. In addition, TSP-1 and -2 stimulate apoptotic pathways in ECs (5). The importance of TSP-1 as a negative regulator of angiogenesis is underscored by the fact that genetic mutations that occur in tumor cells often lead to reduced TSP-1 expression (2). Furthermore, a TSP-1–based therapeutic is currently in clinical trials for the treatment of cancer. Although generally an inhibitor of angiogenesis, TSP-1 has been shown to support angiogenesis in some contexts. This seemingly paradoxical effect stems from the fact that various cell types respond differently to the protein. Whereas TSP-1 inhibits EC migration, it supports vascular smooth muscle cell (VSMC) and inflammatory cell migration. Thus, if the induction of angiogenesis occurs in the presence of inflammation, TSP-1 can appear to promote angiogenesis. In addition, the N-terminal heparin-binding domain of TSP-1 assayed in isolation reportedly stimulates angiogenesis (6). These complex responses arise because TSP-1 and -2 are multifunctional proteins with a wide range of cell surface receptors. The cellular response to these proteins in part depends on which receptors are expressed by a given cell type and which receptors are engaged by the various domains of TSP-1 or -2.