Cyclosporin A differentially inhibits multiple steps in VEGF induced angiogenesis in human microvascular endothelial cells through altered intracellular signaling

The calcineurin inhibitor cyclosporin A (CsA) is a potent immunosuppressive agent that has formed the pharmacologic cornerstone of solid organ transplantation. CsA prevents the activation of lymphokine genes essential for T cell proliferation by disrupting calcium-dependent signal transduction pathways in leukocytes [1]. Although pharmacologic studies of CsA have focused primarily on T cell responses, there is emerging evidence that this agent may exert potent effects on blood vessels, promoting arterial hypertension, inducing long-term vascular dysfunction, and contributing to obliterative vasculopathy in chronic transplant rejection [2-5]. At the present time, chronic rejection with its associated vasculopathy, is the major cause of late allograft dysfunction, including patients with intestinal transplants [6,7].In solid-organ transplantation, the vascular endothelium has received attention because of its unique role as the interface between the donor graft and the host's circulating immune cells, and as a focus of acute rejection [8,9]. More recent investigation has demonstrated that the endothelium plays a central role in chronic rejection, where inappropriate activation of endothelial cells results in obliterative vasculopathy and accelerated post-transplant atherosclerosis [10], a major cause of morbidity and mortality in solid organ transplant recipients. Activation of graft endothelium in chronic rejection may result from host/graft immunologic attack, as well as dysfunction associated with transplant immunosuppression [5]. In transplantation of the small bowel, microvascular dysfunction may contribute to more significant problems with both acute and chronic rejection in these patients. Indeed, small bowel transplantation has been one of the more problematic clinical areas in the realm of solid organ grafts, where patients require increased immunosuppressive regimens and have had overall, less successful clinical outcomes [11-13].The growth of new microvesse