title: Hypoxia-induced modulation of endothelial cell properties: regulation of barrier function and expression of interleukin-6.
abstract: The endothelial cell response to hypoxia involves a range of adaptive mechanisms that reflect an active response of the cell's biosynthetic and metabolic apparatus. Hypoxia-mediated suppression of endothelial barrier function, resulting in increased vascular leakage, is likely to contribute to pulmonary and cerebral edema associated with high altitude and is closely associated with a fall in intracellular cyclic AMP levels. Buttressing 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 shown that supplementation with cyclic AMP analogs or inhibition of endogenous cAMP metabolism enables extension of the time a harvested organ can 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 distinct adaptive mechanism triggered in the endothelium by hypoxia is expression of the cytokine interleukin-6 (IL-6) by a novel mechanism involving transcription driven by the nuclear factor IL-6 (NF-IL-6) DNA binding site in the promoter. IL-6 may exert protective effects on vascular function, thereby limiting vascular injury by a different mechanism than those recruited by elevated cAMP levels. These studies provide insights into tow independent mechanisms through which endothelium responds to oxygen deprivation, and suggest possible new approaches to attentuate vascular injury associated with ischemia.
authors.affiliation: Department of Physiology, Columbia University, College of Physicians and Surgeons, New York, New York, USA.
authors.forename: S F
authors.initials: SF
authors.lastname: Yan
authors.forename: S
authors.initials: S
authors.lastname: Ogawa
authors.forename: D M
authors.initials: DM
authors.lastname: Stern
authors.forename: D J
authors.initials: DJ
authors.lastname: Pinsky
mesh_terms: D000818:Animals; D051743:CCAAT-Enhancer-Binding Protein-delta; D022762:CCAAT-Enhancer-Binding Proteins; D002199:Capillary Permeability; D000242:Cyclic AMP / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004730:Endothelium, Vascular / Q000503:physiopathology*; D015870:Gene Expression; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C497252:CEBPD protein, human; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D009687:Nuclear Proteins; D014157:Transcription Factors; D051743:CCAAT-Enhancer-Binding Protein-delta; D000242:Cyclic AMP