Abstract
The immunosuppressive agent cyclosporin A (CsA), a calcineurin inhibitor which blocks T cell activation has provided the pharmacologic foundation for organ transplantation. CsA exerts additional effects on non-immune cell populations and may adversely effect microvascular endothelial cells, contributing to chronic rejection, a long-term clinical complication and significant cause of mortality in solid-organ transplants, including patients with small bowel allografts. Growth of new blood vessels, or angiogenesis, is a critical homeostatic mechanism in organs and tissues, and regulates vascular populations in response to physiologic requirements. We hypothesized that CsA would inhibit the angiogenic capacity of human gut microvessels. Primary cultures of human intestinal microvascular endothelial cells (HIMEC) were used to evaluate CsA's effect on four in vitro measures of angiogenesis, including endothelial stress fiber assembly, migration, proliferation and tube formation, in response to the endothelial growth factor VEGF. We characterized the effect of CsA on intracellular signaling mechanisms following VEGF stimulation. CsA affected all VEGF induced angiogenic events assessed in HIMEC. CsA differentially inhibited signaling pathways which mediated distinct steps of the angiogenic process. CsA blocked VEGF induced nuclear translocation of the transcription factor NFAT, activation of p44/42 MAPK, and partially inhibited JNK and p38 MAPK. CsA differentially affected signaling cascades in a dose dependent fashion and completely blocked expression of COX-2, which was integrally linked to HIMEC angiogenesis. These data suggest that CsA inhibits the ability of microvascular endothelial cells to undergo angiogenesis, impairing vascular homeostatic mechanisms and contributing to the vasculopathy associated with chronic rejection.
Highlights
The calcineurin inhibitor cyclosporin A (CsA) is a potent immunosuppressive agent that has formed the pharmacologic cornerstone of solid organ transplantation
Because mitogen-activated protein kinases (MAPK) activation has been linked to proliferation of various cell types, including endothelial cells, we performed in vitro growth studies to assess the effect of vascular endothelial growth factor (VEGF) and TNF-α/LPS on human intestinal microvascular endothelial cells (HIMEC)
HIMEC monolayers stimulated with VEGF for 24 hr resulted in a significant increase in cell number, while TNF-α/LPS had essentially no effect and was similar to unstimulated cell growth (Figure 1)
Summary
The calcineurin inhibitor cyclosporin A (CsA) is a potent immunosuppressive agent that has formed the pharmacologic cornerstone of solid organ transplantation. 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 [2,3,4,5]. 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]. 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 [11,12,13]
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