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Estrogen Increases Endothelial Carbon Monoxide, Heme Oxygenase 2, and Carbon Monoxide-Derived cGMP by a Receptor-Mediated System

Department of Obstetrics and Gynecology, Division of Gynecological Endocrinology and Reproductive Medicine (W.T., F.S., W.D., C.S., J.C.H.); Institute of Vascular Biology and Thrombosis Research (Z.Z.); Institute of Forensic Medicine (T.S., W.V.); and Institute for Tumor Biology and Cancer Research (T.W.), University of Vienna Medical School, General Hospital, A-1090 Vienna, Austria

Address all correspondence and requests for reprints to: Walter Tschugguel, M.D., Department of Obstetrics and Gynecology, Division of Gynecological Endocrinology and Reproductive Medicine, University of Vienna Medical School, General Hospital, Waehringer Guertel 18-20, A-1090 Vienna, Austria. E-mail walter.tschugguel{at}akh-wien.ac.at

Abstract

Carbon monoxide, a gaseous activator of soluble guanylyl cyclase formed by a subtype of the enzyme heme oxygenase designated heme oxygenase-2 in vascular endothelium, has been found to dilate blood vessels independently from nitric oxide. Because of the parallels between nitric oxide and carbon monoxide, we speculated that estrogen might affect carbon monoxide production in vascular endothelium. Endothelial cells of human origin (umbilical vein and uterine artery) were incubated for 4 or 24 h with 10^-12–10^-6 M 17ß-estradiol. 17ß-Estradiol, at a concentration such as that attained during the ovulatory phase of the menstrual cycle (10^-10 M), administrated for 4 h led to a 2-fold increase in intracellular carbon monoxide production and heme oxygenase-2 protein levels (P < 0.05). A reporter assay, measuring the formation of cGMP as the direct product of carbon monoxide-induced activation of soluble guanylyl cyclase in endothelial cells, also revealed a 56% increase in cellular cGMP after treatment with 10^-10 M E₂ 17ß-estradiol (P < 0.05). By contrast, higher 17ß-estradiol concentrations had no significant respective effects due to nitric oxide synthase inhibition of carbon monoxide release. This 17ß-estradiol effect appeared to be ER dependent, as preincubation with tamoxifen (10^-6 M) blocked the stimulatory effect of 17ß-estradiol in each instance. Our preliminary data indicate a potential role for carbon monoxide as a biological messenger molecule in estrogen-mediated regulation of vascular tone.

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