The microvascular cell and ischemia-reperfusion injury

The vascular endothelium has a number of functions that may mediate many of the ischemia-reperfusion (IR) phenomena. The gatekeeper function is disturbed and increased capillary permeability results in edema and organ dysfunction. Vasomotor function is altered, with impairment of relaxation and augmentation of constrictor responses. Coagulation becomes imbalanced, favoring the procoagulant pathways that lead to thrombosis. Vascular adhesion molecules (integrins, selectins) are upregulated or expressed to mediate the adherence and subsequent destructive effects of neutrophils as they interact with the endothelium and the underlying organs. Finally, the more chronic vascular endothelial response may be proliferation of all cellular components of the vessel wall, leading, e.g., to intimal hyperplasia or restenosis. Ultimately, the endothelium plays a significant role either in the reparative processes that lead to recovery of the organ (myocardial stunning) or in the destructive processes that lead to cell or organ death (myocardial infarction). Our research group has been interested in the selectins, particularly E-selectin (endothelial) and P-selectin (platelet). E-selectin is not constitutively present on endothelial cells but can be upregulated by inflammatory mediators such as the cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and endotoxin. We have investigated the upregulation of E-selectin with cytokines in both hypoxia and hypothermia. Hypoxia appears to enhance E-selectin upregulation on stimulation with IL-1 or TNF-alpha, although hypothermia (to 25 degrees C) blunts this response. With rewarming to 37 degrees C, the transduction and surface expression return.