title: Estrogens inhibit angiotensin II-induced leukocyte-endothelial cell interactions in vivo via rapid endothelial nitric oxide synthase and cyclooxygenase activation.
abstract: Angiotensin II (Ang II) may be a key molecule in the development of atherosclerosis. Because the incidence of coronary atherosclerosis in premenopausal women is lower than that observed in men or postmenopausal women, we have investigated the effect of estrogens on Ang II-induced leukocyte recruitment in vivo using intravital microscopy in the rat mesenteric microcirculation. Superfusion for 60 minutes with Ang II induced a significant increase in leukocyte rolling flux, adhesion, and emigration. Administration of 17-beta-estradiol (17-beta-E) after 30 minutes of Ang II superfusion produced a reduction of these leukocyte responses by 55.1%, 72.7%, and 70.9%, respectively, an additional 30 minutes later. The effect observed with 17-beta-E was receptor-mediated and specific. 17-beta-E superfusion did not modify either L-NAME or indomethacin-induced leukocyte responses. Inhibitory responses caused by 17-beta-E were not altered by either 7-nitroindazole or actinomycin D cosuperfusion. Stimulation of endothelial cells with 17-beta-E caused a rapid and dose-dependent release of prostacyclin. Finally, tamoxifen or ICI 182,780 administration provoked a significant increase in leukocyte-endothelial cell interactions 90 minutes later, which were significantly attenuated by systemic preadministration with an Ang II AT(1) receptor antagonist. Tamoxifen-induced leukocyte responses were also reduced by systemic pretreatment with an anti-P-selectin mAb and an anti-CD18 mAb. Hence, the antiatherogenic effects of estrogens may be mediated by inhibition of Ang II-induced leukocyte recruitment through endothelial NO and prostacyclin release. Furthermore, scarcity of estrogens resulted in decreased levels of vasodilators and the exposure of the endothelium to the deleterious action of Ang II, which may explain the higher incidence of coronary atherosclerosis in men and postmenopausal women.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Clinic Hospital, University of Valencia, Spain.
authors.forename: Angeles
authors.initials: A
authors.lastname: Alvarez
authors.forename: Carlos
authors.initials: C
authors.lastname: Hermenegildo
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Issekutz
authors.forename: Juan V
authors.initials: JV
authors.lastname: Esplugues
authors.forename: Maria-Jesus
authors.initials: MJ
authors.lastname: Sanz
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D019808:Losartan / Q000494:pharmacology; D008208:Lymphatic System / Q000166:cytology / Q000276:immunology; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D013152:Splanchnic Circulation / Q000502:physiology
chemical_list: D057911:Angiotensin Receptor Antagonists; D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D004967:Estrogens; D044140:Receptor, Angiotensin, Type 1; D020845:Selective Estrogen Receptor Modulators; D000804:Angiotensin II; D004958:Estradiol; D011464:Epoprostenol; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; D019808:Losartan