The role of thrombospondin-1 in cardiovascular health and pathology.

Cardiovascular diseases (CVDs) remain a leading cause of morbidity and mortality in the developed world and are becoming increasingly prevalent in the developing world. Although a range of therapies already exist for established CVDs, there is a significant interest in further understanding disease pathogenesis in order to improve treatment. Thrombospondin (TSP)-1 is an important extracellular matrix component that influences the function of vascular smooth muscle cells, endothelial cells, fibroblasts and inflammatory cells with important implications for CVDs. TSP-1 regulates matrix production and organisation thereby influencing tissue remodelling and promoting the generation of T regulatory cells that control the inflammatory response. Reported findings from in vitro and animal studies are conflicting and suggest differing effects of TSP-1 on various cellular mechanisms, depending on the experimental setting. Vascular cells express a number of TSP-1 receptors, such as CD36, proteoglycans and several integrins, which are regulated by specific contextual signals which may explain the varying effects that TSP-1 elicits in different environments. Different domains of TSP-1 activate distinct signalling pathways eventually resulting in quite different cellular phenotypes and tissue specific effects. The sum total of the various pathways activated likely determines the overall effect on angiogenesis or proliferation in a specific tissue. Hence defining a common mechanism of action of TSP-1 in CVD is complicated. Increasing the understanding of the role of TSP-1 in various CVDs will potentially provide new opportunities for therapeutic intervention using peptides derived from its various domains currently under evaluation in other diseases.