Estradiol-induced attenuation of pulmonary hypertension is not associated with altered eNOS expression

Vascular Physiology Group, Department of Cell Biology and Physiology, Health Sciences Center, University of New Mexico, Albuquerque, New Mexico 87131-5218 Female rats develop less severe pulmonary hypertension (PH) in response to chronic hypoxia compared with males, thus implicating a potential role for ovarian hormones in mediating this gender difference. Considering that estrogen upregulates endothelial nitric oxide (NO) synthase (eNOS) in systemic vascular tissue, we hypothesized that estrogen inhibits hypoxic PH by increasing eNOS expression and activity. To test this hypothesis, we examined responses to the endothelium-derived NO-dependent dilator ionomycin and the NO donors S -nitroso- N -acetylpenicillamine and spermine NONOate in U-46619-constricted, isolated, saline-perfused lungs from the following groups: 1 ) normoxic rats with intact ovaries, 2 ) chronic hypoxic (CH) rats with intact ovaries, 3 ) CH ovariectomized rats given 17 -estradiol (E 2 ), and 4 ) CH ovariectomized rats given vehicle. Additional experiments assessed pulmonary eNOS levels in each group by Western blotting. Our findings indicate that E 2 attenuated chronic hypoxia-induced right ventricular hypertrophy, pulmonary arterial remodeling, and polycythemia. Furthermore, although CH augmented vasodilatory responsiveness to ionomycin and increased pulmonary eNOS expression, these responses were not potentiated by E 2 . Finally, responses to S -nitroso- N -acetylpenicillamine and spermine NONOate were similarly attenuated in all CH groups compared with normoxic control groups. We conclude that the inhibitory influence of E 2 on chronic hypoxia-induced PH is not associated with increased eNOS expression or activity. chronic hypoxia; right ventricular hypertrophy; vascular remodeling; nitric oxide-dependent vasodilation; endothelial nitric oxide synthase