THERAPEUTIC POTENTIAL OF TARGETING ANIGIOGENESIS IN CHRONIC REJECTION AND ISCHEMIA-REPERFUSION INJURY IN SMALL BOWEL TRANSPLANTATION

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Vascular endothelial growth factor (VEGF), a major angiogenesis factor, also plays a critical role as a proinflammatory cytokine in various immune responses. Since it is well known to be induced by hypoxia, it may be a critical mediator in the ischemic injury. To date, however, little is known of its role in intestinal ischemia reperfusion (IR) injury. In this study, we investigated the role of VEGF and its receptors (VEGFR-1 and VEGFR-2) during the intestinal IR injury.Intestinal injury was elicited through clamping of the superior mesenteric artery for 45 followed by reperfusion. The local expression of VEGF was significantly upregulated after reperfusion following ischemia compared to controls suggesting that VEGF and VEGFR may play an important role in the initiation of intestinal I/R injury. To confirm the pathophysiological roles of each VEGFR, we utilized specific neutralizing monoclonal antibodies for each VEGFR. Mice were treated with control IgG or anti-VEGFR mAbs 30 minutes before reperfusion. The simultaneous blockade of two VEGFRs significantly prolonged the survival. By histological analysis, mucosal sloughing and villi destruction were observed in control mice, while these mucosal damages were significantly reduced in mice treated with simultaneous VEGFR blockade. Data are suggestive that both VEGFRs are critical and function synergistically in vivo. The protective effect was associated with the downregulation of local expressions of cytokines. Data demonstrates that VEGF and VEGFR are functional in intestinal I/R injury and targeting VEGF/VEGFR pathway may represent a novel therapy for the protection of the posttransplant intestinal I/R injury.We also found that targeting angiogenesis has significant protective effect on the prevention of chronic rejection using MHC class II-mismatched cardiac transplantation model.