Importance of estrogen metabolites.

T he influence of estrogen on blood pressure is complicated and sometimes contradictory. Premenopausal women have a lower incidence of hypertension, but recent clinical trials suggest that postmenopausal hormone replacement therapy does not necessarily decrease the risk of cardiovascular disease. Sexually dimorphic hypertension is evident in multiple animal models, yet only some indicate a critical role for estrogen. 1 These contradictions emphasize the importance of identifying the critical molecular signaling pathways in the cardiovascular system that are activated by estrogen and pursuing alternative pathways for their activation. One important factor that has been neglected in the study of estrogen's cardiovascular effects is the conversion of 17-β-estradiol, the most commonly studied ovarian estrogen, to metabolites that are capable of exerting discrete physiological effects (Figure). In this issue of Hypertension, Jennings et al 2 use a mouse model of angiotensin II (Ang II)−induced hypertension to demonstrate that the protective cardiovascular effects historically attributed to the predominant estrogen 17-β-estradiol may instead reflect distinct actions by the metabolite 2-methoxyestradiol (2-MeE2). The critical enzymes include cytochrome P450 1B1 (CYP1B1), which metabolizes 17-β-estradiol to the catechol estrogen 2-hydroxyestradiol (2-OHE), and catechol-O-methyl transferase, which subsequently converts 2-OHE to 2-MeE2. In comparison with wild-type controls, female CYP1B1-knockout mice display a significantly greater pressor response to Ang II accompanied by vascular and cardiac remodeling, vascular dysfunc-tion, and oxidative stress. This genetic approach is nicely complemented by studies using the selective CYP1B1 inhibi-tor tetramethoxystilbene, which similarly increases the Ang II response. The ability of both CYP1B1 gene deletion and pharmacological inhibition to enhance Ang II–induced hyper-tension is absent in ovariectomized mice, emphasizing the necessity of endogenous estrogen as a substrate for CYP1B1's protective actions. Protection from Ang II–induced hypertension is restored in CYP1B1-knockout mice by administration of the CYP1B1 product 2-OHE and its catechol-O-methyl transferase–derived metabolite 2-MeE2. Interestingly, treatment with another catechol estrogen, 4-OHE, does not reduce blood pressure in Ang II–infused CYP1B1-knockout mice and exacerbates the Ang II response in wild-type female mice. The increased pressure may result from the actions of 4-OHE or its metabolite 4-MeE2. The contradictory actions of these 2 catechol estro-gens indicate that in wild-type female mice, 17-β-estradiol is predominantly metabolized to 2-OHE and 2-MeE2, which have beneficial actions on blood pressure. Whether disease or aging alter the predominant metabolic pathway and lead to increased production of detrimental metabolites is not yet known. 2-MeE2 may have direct actions on the renin–angiotensin system or may counteract …