Estrogen increases endothelial carbon monoxide, heme oxygenase 2, and carbon monoxide-derived cGMP by a receptor-mediated system

Carbon monoxide, a gaseous activator of soluble guanylyl cyclase formed by a subtype of the enzyme heme oxygenase designated heme oxygenase-2 in vascu lar endothelium, has been found to dilate blood vessels independently from nitric oxide. Because of the parallels between nitric oxide and carbon mono xide, we speculated that estrogen might affect carbon monoxide production i n vascular endothelium. Endothelial cells of human origin (umbilical vein a nd uterine artery) were incubated for 4 or 24 h with 10(-12)-10(-6) M 17 be ta -estradiol. 17 beta -Estradiol, at a concentration such as that attained during the ovulatory phase of the menstrual cycle (10(-10) m), administrat ed for 4 h led to a 2-fold increase in intracellular carbon monoxide produc tion and heme oxygenase-2 protein levels (P < 0.05). A reporter assay, meas uring the formation of cGMP as the direct product of carbon monoxide-induce d activation of soluble guanylyl cyclase in endothelial cells, also reveale d a 56% increase in cellular cGMP after treatment with 10(-10) m E-2 17<bet a>-estradiol (P < 0.05). By contrast, higher 17<beta>-estradiol concentrati ons had no significant respective effects due to nitric oxide synthase inhi bition of carbon monoxide release. This 17 beta -estradiol effect appeared to be ER dependent, as preincubation with tamoxifen (10(-6) m) blocked the stimulatory effect of 17 beta -estradiol in each instance. Our preliminary data indicate a potential role for carbon monoxide as a biological messenge r molecule in estrogen-mediated regulation of vascular tone.