In the balance: how do thrombospondins contribute to the cellular pathophysiology of cardiovascular disease?

Thrombospondins (TSPs) are multidomain, secreted proteins that associate with cell surfaces and extracellular matrix. In mammals, there is a large body of data on functional roles of various TSP family members in cardiovascular disease (CVD), including stroke, cardiac remodeling and fibrosis, atherosclerosis, and aortic aneurysms. Coding single nucleotide polymorphisms (SNPs) of TSP1 or TSP4 are also associated with increased risk of several forms of CVD. Whereas interactions and functional effects of TSPs on a variety of cell types have been studied extensively, the molecular and cellular basis for the differential effects of the SNPs remains under investigation. Here, we provide an integrative review on TSPs, their roles in CVD and cardiovascular cell physiology, and known properties and mechanisms of TSP SNPs relevant to CVD. In considering recent expansions to knowledge of the fundamental cellular roles and mechanisms of TSPs, as well as the effects of wild-type and variant TSPs on cells of the cardiovascular system, we aim to highlight knowledge gaps and areas for future research or of translational potential.