Chronic Hypoxia Inhibits Sex Steroid Hormone-Mediated Attenuation of Ovine Uterine Arterial Myogenic Tone in Pregnancy

Previous studies in ovine uterine arteries have demonstrated that sex steroid hormones upregulate extracellular signal-regulated kinase 1/2 expression and downregulate the protein kinase C signaling pathway, resulting in the attenuated myogenic tone in pregnancy. The present study tested the hypothesis that chronic hypoxia during gestation inhibits the sex steroid-mediated adaptation of extracellular signal-regulated kinase 1/2 and protein kinase C signaling pathways and increases the myogenic tone of uterine arteries. Uterine arteries were isolated from nonpregnant and near-term pregnant sheep that had been maintained at sea level (≈300 m) or exposed to high-altitude (3801 m) hypoxia for 110 days. In contrast to the previous findings in normoxic animals, 17β-estradiol and progesterone failed to suppress protein kinase C-induced contractions and the pressure-induced myogenic tone in uterine arteries from hypoxic animals. Western analyses showed that the sex steroids lost their effects on extracellular signal-regulated kinase 1/2 expression and phospho- extracellular signal-regulated kinase 1/2 levels, as well as the activation of protein kinase C isozymes in uterine arteries of hypoxic ewes. In normoxic animals, pregnancy and the sex steroid treatments significantly increased uterine artery estrogen receptor-α and progesterone receptor B expression. Chronic hypoxia selectively downregulated estrogen receptor-α expression in uterine arteries of pregnant animals and eliminated the upregulation of estrogen receptor-α in pregnancy or by the steroid treatments observed in normoxic animals. The results demonstrate that, in the ovine uterine artery, chronic hypoxia in pregnancy inhibits the sex steroid hormone-mediated adaptation of decreased myogenic tone by downregulating estrogen receptor-α expression, providing a mechanism linking hypoxia and maladaptation of uteroplacental circulation and an increased risk of preeclampsia in pregnancy.