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

血管内皮生长因子(VEGF)是一种重要的血管生成因子，在多种免疫反应中也发挥重要的促炎细胞因子作用。由于众所周知，它是由低氧诱导的，因此它可能是缺血性损伤的关键介质。然而，到目前为止，对其在肠缺血再灌注损伤中的作用知之甚少。本研究旨在探讨血管内皮生长因子及其受体(VEGFR-1和VEGFR-2)在肠缺血再灌注损伤中的作用。缺血再灌注后局部血管内皮生长因子表达明显上调，提示血管内皮生长因子及其受体可能在肠I/R损伤的发生中起重要作用。为了确认每个VEGFR的病理生理学作用，我们使用了针对每个VEGFR的特异性中和单抗。小鼠于再灌注前30min分别给予对照免疫球蛋白或抗VEGFR单抗治疗。同时阻断两个VEGFRs可显著延长小鼠的存活时间。通过组织学分析，对照组小鼠的粘膜塌陷和绒毛破坏，而同时应用VEGFR阻断剂的小鼠，这些粘膜损伤明显减轻。数据提示，这两种血管内皮生长因子受体在体内都是关键的和协同作用的。其保护作用与下调局部细胞因子的表达有关。研究结果表明，血管内皮生长因子及其受体在肠I/R损伤中发挥重要作用，靶向血管生成通路可能成为保护移植后肠I/R损伤的一种新的治疗方法。我们还发现，靶向血管生成对MHC-II类不相合心脏移植模型的慢性排斥反应有明显的保护作用。

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.