HYPOXIA AND MODIFICATION OF THE ENDOTHELIUM - IMPLICATIONS FOR REGULATION OF VASCULAR HOMEOSTATIC PROPERTIES

Hypoxia is a common denominator of ischemic microenvironments. Endothe lium subjected to oxygen deprivatian maintains cell viability and basi c biosynthetic mechanisms, but displays multiple changes in properties relevant to vascular homeostasis, including suppression of the antico agulant cofactor thrombomodulin, decreased barrier function, and gener ation of proinflammatory cytokines. Diminished intracellular cAMP duri ng the period of hypoxia and lowered nitric oxide/cGMP in the subseque nt reperfusion period are proposed as fundamental mechanisms driving v ascular dysfunction impacting on coagulation permeability, vasomotor t one and leuckocyte adhesivity. The period of organ preservation for tr ansplantation recognized to be associated with hypoxia, primes mechani sms leading to subsequent vascular dysfunction which can be ameliorate d by buttressing cAMP and nitric oxide/cGMP intra- and intercellular s econd messenger systems. A mechanism likely to contribute to hypoxia-m ediated generation of cytokines, such as interleukin 6, is activation of the transcription factor NF-IL-6, which occurs in oxygen deprivatio n. These data indicate that study of cellular mechanisms of endothelia l perturbation in hypoxia is likely to provide insights ultimately app licable to ischemia-induced vascular damage.