Influence of 2‐Methoxyestradiol and Sex on Hypoxia‐Induced Pulmonary Hypertension and Hypoxia‐Inducible Factor‐1‐α

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Abstract
Background: Women are at greater risk of developing pulmonary arterial hypertension, with estrogen and its downstream metabolites playing a potential role in the pathogenesis of the disease. Hypoxia‐inducible factor‐1‐α (HIF 1α) is a pro‐proliferative mediator and may be involved in the development of human pulmonary arterial hypertension . The estrogen metabolite 2‐methoxyestradiol (2 ME 2) has antiproliferative properties and is also an inhibitor of HIF 1α. Here, we examine sex differences in HIF 1α signaling in the rat and human pulmonary circulation and determine if 2 ME 2 can inhibit HIF 1α in vivo and in vitro. Methods and Results: HIF 1α signaling was assessed in male and female distal human pulmonary artery smooth muscle cells ( hPASMC s), and the effects of 2 ME 2 were also studied in female hPASMC s. The in vivo effects of 2 ME 2 in the chronic hypoxic rat (male and female) model of pulmonary hypertension were also determined. Basal HIF 1α protein expression was higher in female hPASMC s compared with male. Both factor‐inhibiting HIF and prolyl hydroxylase‐2 (hydroxylates HIF leading to proteosomal degradation) protein levels were significantly lower in female hPASMC s when compared with males. In vivo, 2 ME 2 ablated hypoxia‐induced pulmonary hypertension in male and female rats while decreasing protein expression of HIF 1α. 2 ME 2 reduced proliferation in hPASMC s and reduced basal protein expression of HIF 1α. Furthermore, 2 ME 2 caused apoptosis and significant disruption to the microtubule network. Conclusions: Higher basal HIF 1α in female hPASMC s may increase susceptibility to developing pulmonary arterial hypertension . These data also demonstrate that the antiproliferative and therapeutic effects of 2 ME 2 in pulmonary hypertension may involve inhibition of HIF 1α and/or microtubular disruption in PASMC s.

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