Estrogens and Development of Pulmonary Hypertension: Interaction of Estradiol Metabolism and Pulmonary Vascular Disease

Abstract

Severe pulmonary arterial hypertension (PAH) is characterized by clustered proliferation of endothelial cells in the lumina of small size pulmonary arteries resulting in concentric obliteration of the lumina and formation of complex vascular structures known as plexiform lesions. This debilitating disease occurs more frequently in women, yet both animal studies in classical models of PAH and limited clinical data suggest protective effects of estrogens: the estrogen paradox in pulmonary hypertension. Little is known about the role of estrogens in PAH, but one line of evidence strongly suggests that the vascular protective effects of 17β-estradiol (estradiol; E2) are mediated largely by its downstream metabolites. Estradiol is metabolized to 2-hydroxyestradiol (2HE) by CYP1A1/CYP1B1, and 2HE is converted to 2-methoxyestradiol (2ME) by catechol-Omethyl transferase. 2ME is extensively metabolized to 2-methoxyestrone, a metabolite that lacks biologic activity but which may be converted back to 2ME. 2ME has no estrogenic activity and its effects are mediated by estrogen receptors-independent mechanism(s). Notably, in systemic and pulmonary vascular endothelial cells, smooth muscle cells, and fibroblasts 2ME exerts stronger anti-mitotic effects than E2 itself. E2 and 2ME, despite having similar effects on other cardiovascular cells, have opposing effects on endothelial cells; that is, in endothelial cells, E2 is pro-mitogenic, pro-angiogenic and anti-apoptotic, whereas 2ME is antimitogenic, anti-angiogenic and pro-apoptotic. This may have significant ramifications in severe PAH that involves uncontrolled proliferation of monoclonal, apoptosis resistant endothelial cells. Based on its cellular effects, 2ME should be expected to attenuate the progression of disease and provide protection in severe PAH. In contrast, E2, due to its mitogenic, angiogenic, and anti-apoptotic effects (otherwise desirable in normal, quiescent endothelial cells), may even adversely affect endothelial remodeling in PAH and this may be even more significant if the E2's effects on injured endothelium are not opposed by 2ME (e.g., in the event of reduced E2 conversion to 2ME due to hypoxia, inflammation, drugs, environmental factors, or genetic polymorphism of metabolizing enzymes). This review focuses on the effects of estrogens and their metabolites on pulmonary vascular pathobiology and the development of experimental PAH, and offers potential explanation for the estrogen paradox in PAH. Furthermore, we propose that unbalanced estradiol metabolism may lead to the development of PAH. Recent animal data and studies in patients with PAH support this concept.Corresponding Author: Stevan P. Tofovic M.D., Ph.D. FAHA FASN Division of Pulmonary, Allergy and Critical Care Medicine and Vascular Medicine Institute, Department of Medicine University of Pittsburgh School of Medicine Bridge side 542 100 Technology Drive, Pittsburgh, PA 15219 FAX +412-624-5070 Phone +412-648-3363 tofovic@dom.pitt.edu. This is a PDF file of an unedited manuscript that ...

Estrogens in Men: Another Layer of Complexity of Estradiol Metabolism in Pulmonary Hypertension

“…Nonetheless, the primary human estrogen 17b-estradiol (estradiol) exerts beneficial, rather than detrimental, effects in classical models of PAH (i.e., hypoxia-and monocrotaline-induced PAH). This puzzling inconsistency is called the "estrogen paradox" (2). The apparent contradictions posed by the effects of female sex and estrogens in experimental PAH versus human PAH could be explained by the limitations of the experimental models used and the opposite roles estradiol may play in the pulmonary vasculature versus the right ventricle ( Figure 1C).…”

“…The fact that pulmonary arterial hypertension (PAH) is more common in women than in men (1) suggests that estrogens importantly contribute to the pathophysiology of PAH (2). Nonetheless, the primary human estrogen 17b-estradiol (estradiol) exerts beneficial, rather than detrimental, effects in classical models of PAH (i.e., hypoxia-and monocrotaline-induced PAH).…”

“…The apparent contradictions posed by the effects of female sex and estrogens in experimental PAH versus human PAH could be explained by the limitations of the experimental models used and the opposite roles estradiol may play in the pulmonary vasculature versus the right ventricle ( Figure 1C). Although the estrogen paradox remains unresolved, mounting evidence (both in patients with PAH and in novel rodent models of angioproliferative PAH) suggests that precursors and metabolites of sex steroids influence the development and progression of PAH and could account for the estrogen paradox (2,3).…”

“…In this regard, the 2-hydroxylation-catechol-O-methyltransferase pathway produces nonestrogenic, antiproliferative, antiangiogenic, and antiinflammatory metabolites (2-hydroxyestradiol and 2-methoxyestradiol), and these metabolites are protective in hypoxia-, monocrotaline-, sugene 1 hypoxia-, and bleomycin-induced PAH (2). In contrast, the 4-hydroxylation and 16-hydroxylation pathways produce 4-hydroxyestradiol and 16a-hydroxyestrone, which are estrogenic, very reactive, and exert significant mitogenic, angiogenic, and inflammatory actions (2,3,10).…”

“…Since the first report that 2-methoxyestradiol (major nonestrogenic metabolite of estradiol) attenuates the development and progression of monocrotaline-induced PAH (9), it has become increasingly clear that estradiol precursors, estradiol per se, and estradiol metabolites can exhibit both detrimental and protective effects in PAH (2,3). In this regard, the 2-hydroxylation-catechol-O-methyltransferase pathway produces nonestrogenic, antiproliferative, antiangiogenic, and antiinflammatory metabolites (2-hydroxyestradiol and 2-methoxyestradiol), and these metabolites are protective in hypoxia-, monocrotaline-, sugene 1 hypoxia-, and bleomycin-induced PAH (2).…”