HYPOXIA-INDUCED MODULATION OF ENDOTHELIAL-CELL PROPERTIES - REGULATION OF BARRIER FUNCTION AND EXPRESSION OF INTERLEUKIN-6

Hypoxia-induced modulation of endothelial cell properties: Regulation of barrier function and expression of interleukin-6. The endothelial c ell response to hypoxia involves a range of adaptive mechanisms that r eflect an active response of the cell's biosynthetic and metabolic app aratus. Hypoxia-mediated suppression of endothelial barrier function, resulting in increased vascular leakage, is likely to contribute to pu lmonary and cerebral edema associated with high altitude and is closel y associated with a fall in intracellular cyclic AMP levels. Buttressi ng of this second messenger pathway in the endothelium using membrane permeant cyclic AMP analogs prevents increased vascular leakage due to hypoxia. Application of this principle to organ preservation has show n that supplementation with cyclic AMP analogs or inhibition of endoge nous cAMP metabolism enables extension of the time a harvested organ c an remain extracorporeally, after which transplantation is successful. The underlying mechanism through which cyclic AMP exerts its effects appears to be maintenance of vascular homeostasis in the graft. A dist inct adaptive mechanism triggered in the endothelium by hypoxia is exp ression of the cytokine interleukin-6 (IL-6) by a novel mechanism invo lving transcription driven by the nuclear factor IL-6 (NF-IL-6) DNA bi nding site in the promoter. IL-6 map exert protective effects on vascu lar function, thereby limiting vascular injury by a different mechanis m than those recruited by elevated cAMP levels. These studies provide insights into two independent mechanisms through which endothelium res ponds to oxygen deprivation, and suggest possible new approaches to at tentuate vascular injury associated with ischemia.