The pathophysiological mechanisms involved in ischemia-reperfusion injury are poorly understood. Although transforming growth factor (TGF)-β has been shown to provide protection against ischemia-reperfusion injury in different organ systems, little is known about the regulation of TGF-β action during this process. Here we analyzed the effect of ischemia and reperfusion on the expression of TGF-β and its receptors in vivo with a pig skin flap model. Analysis of unoperated skin, nonischemic control flap, ischemic flap, and reperfused flap by immunohistochemistry indicates that ischemia and reperfusion result in rapid and dynamic regulation of type I, II, and III TGF-β receptors and TGF-β1 in a cell type-specific manner. Furthermore, hypoxia upregulates type II TGF-β receptor mRNA in skin fibroblasts in culture. Together, our results reveal that TGF-β receptors and TGF-β1 are markedly increased under acute ischemic conditions in the blood vessels and fibroblasts of the skin. We conclude that TGF-β action is enhanced under ischemic conditions and that it may represent an adaptive response to ischemic injury. The augmented TGF-β responsiveness may be a critical determinant of the protective effect of TGF-β during ischemia-reperfusion injury.