Vascular protection by estrogen in ischemia-reperfusion injury requires endothelial nitric oxide synthase.
Estrogen increases nitric oxide (NO) production by inducing the activity of endothelial NO synthase (eNOS) (Simoncini et al. Nature 407: 538, 2000). Ischemia (30 min) and reperfusion (I/R) increased the number of adherent leukocytes and decreased their rolling velocities in mouse cremaster muscle venules with a strong dependence on wall shear rate. Minimum rolling velocity at approximately 5 min after the onset of reperfusion was accompanied by increased P-selectin expression. This preceded the peak in leukocyte adhesion (at 10-15 min). In untreated wild-type mice, I/R caused a decrease of leukocyte rolling velocity from 37 to 26 microm/s and a 2.0-fold increase in leukocyte adhesion. Both were completely abolished by 0.25 mg ip estrogen 1 h before surgery. In eNOS(-/-) mice, the decrease of leukocyte rolling velocity and increase in adhesion were similar but were only marginally improved by estrogen. We conclude that the protective effect of estrogen, as measured by leukocyte rolling and adhesion, is significantly reduced in eNOS(-/-) mice, suggesting that induction of eNOS activity is the major mechanism of vasoprotection by estrogen in this model.
Prorock
Alyson J
AJ
Department of Biomedical Engineering, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Hafezi-Moghadam
Ali
A
Laubach
Victor E
VE
Liao
James K
JK
Ley
Klaus
K
D000009:Abdominal Muscles / Q000098:blood supply*; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000503:physiopathology; D002448:Cell Adhesion / Q000502:physiology; D019610:Cytoprotection; D004967:Estrogens / Q000494:pharmacology*; D006439:Hemodynamics; D007511:Ischemia / Q000503:physiopathology*; D007962:Leukocytes / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D019001:Nitric Oxide Synthase / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019007:P-Selectin / Q000378:metabolism; D015427:Reperfusion Injury / Q000503:physiopathology*; D013997:Time Factors
D004967:Estrogens; D019007:P-Selectin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse