(A) Activities of 2-hydroxylation, 16α-hydroxylation and 17β–HSD pathways determine the overall biological effects of E2 in PAH. (B) In endothelial cells, 2-methoxyestradiol (2ME) is a more potent modulator of prostacyclin, endothelin and nitric oxide synthesis/release than estradiol (E2); 2ME and E2 have opposite effects on endothelial pathobiology in PAH (2HE, 2-Hydroxyestradiol; 2ME1, 2-Methoxyestrone; E3, Estriol; 16αE1 , 16α–Estrone).