Hypoxia and modification of the endothelium: implications for regulation of vascular homeostatic properties.
Hypoxia is a common denominator of ischemic microenvironments. Endothelium subjected to oxygen deprivation maintains cell viability and basic biosynthetic mechanisms, but displays multiple changes in properties relevant to vascular homeostasis, including suppression of the anticoagulant cofactor thrombomodulin, decreased barrier function, and generation of proinflammatory cytokines. Diminished intracellular cAMP during the period of hypoxia and lowered nitric oxide/cGMP in the subsequent reperfusion period are proposed as fundamental mechanisms driving vascular dysfunction impacting on coagulation, permeability, vasomotor tone and leukocyte adhesivity. The period of organ preservation for transplantation, recognized to be associated with hypoxia, primes mechanisms leading to subsequent vascular dysfunction which can be ameliorated by buttressing cAMP and nitric oxide/cGMP intra- and intercellular second messenger systems. A mechanism likely to contribute to hypoxia-mediated generation of cytokines, such as interleukin 6, is activation of the transcription factor NF-IL-6, which occurs in oxygen deprivation. These data indicate that study of cellular mechanisms of endothelial perturbation in hypoxia is likely to provide insights ultimately applicable to ischemia-induced vascular damage.
Pinsky
D J
DJ
Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
Yan
S F
SF
Lawson
C
C
Naka
Y
Y
Chen
J X
JX
Connolly
E S
ES
Stern
D M
DM
D000818:Animals; D001483:Base Sequence; D015687:Cell Hypoxia; D016207:Cytokines / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D006706:Homeostasis; D006801:Humans; D008969:Molecular Sequence Data; D009926:Organ Preservation / Q000379:methods; D010100:Oxygen / Q000378:metabolism*
D016207:Cytokines; D010100:Oxygen