Healing the vasculature: angioprotective therapy moves from the bench to the clinic

Advances in immunosuppression have extended the lifetime of most types of organ grafts, leading to improved long-term outcomes after transplantation. The fact that death of the transplant patient with a functioning graft currently represents the leading cause of late graft loss is sometimes viewed as testament to this success. However, this interpretation is misleading because patient death often results from the systemic effects of immunosuppressive treatment. Prominent among the latter are atherosclerosis, infection, and malignancy. Vascular disease, manifesting as transplant arteriopathy, also contributes to chronic allograft failure, another major cause of late graft loss. Overall, arteriosclerosis (systemic and graft specific) accounts for about 50% of late graft loss, making it a compelling therapeutic priority that has yet to be effectively tackled in the clinic. The advent of novel immunosuppressive compounds with angioprotective properties and a tighter control of metabolic risk factors for vascular disease have the potential to overcome this obstacle and further improve transplant outcomes. Targeted modulation of growth factor and hormone receptor activity by nonimmunosuppressive, low-molecular-weight compounds represents a complementary approach to this problem. Here we trace the development and assess the potential of the most promising angioprotective therapies currently in, or approaching, the clinic and outline a structured rationale for their efficient evaluation.