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Chronic hypoxia inhibits sex steroid hormone-mediated attenuation of ovine uterine arterial myogenic tone in pregnancy.

ABSTRACT: 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, 17?-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-? and progesterone receptor B expression. Chronic hypoxia selectively downregulated estrogen receptor-? expression in uterine arteries of pregnant animals and eliminated the upregulation of estrogen receptor-? 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-? expression, providing a mechanism linking hypoxia and maladaptation of uteroplacental circulation and an increased risk of preeclampsia in pregnancy.

SUBMITTER: Chang K

PROVIDER: S-EPMC2940959 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Chronic hypoxia inhibits sex steroid hormone-mediated attenuation of ovine uterine arterial myogenic tone in pregnancy.

Chang Katherine K Xiao DaLiao D Huang Xiaohui X Xue Zhice Z Yang Shumei S Longo Lawrence D LD Zhang Lubo L

Hypertension (Dallas, Tex. : 1979) 20100726 4

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 t ...[more]

PMID: 20660818

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Project description:Gestational hypoxia inhibits steroid hormone-induced upregulation of Ca(2+)-activated K(+) (KCa) channel activities in uterine arteries. We tested the hypothesis that increased reactive oxygen species play an important role in hypoxia-mediated inhibition of KCa channel activities. Uterine arteries were isolated from nonpregnant (nonpregnant uterine artery) and near-term (?142-145 day) pregnant (pregnant uterine artery) sheep maintained at either sea level or high altitude (3820 m, Pao2: 60 mm Hg) for 110 days. In pregnant uterine arteries, hypoxia significantly decreased large conductance channel opener NS1619- and small conductance channel opener NS309-induced relaxations, which were partially restored by reactive oxygen species inhibitor N-acetylcysteine (NAC). NAC significantly increased large conductance KCa but not small conductance KCa current densities in uterine arterial smooth muscle cells in pregnant animals acclimatized to high altitude. The NAC-sensitive component of small conductance KCa-induced relaxations was diminished in endothelium-denuded arteries. In nonpregnant uterine arteries, NS1619- and NS309-induced relaxations were diminished compared with those in pregnant uterine arteries. Treatment of nonpregnant uterine arteries with 17?-estradiol and progesterone for 48 hours increased small conductance KCa type 3 protein abundance and NS1619- and NS309-induced relaxations, which were inhibited by hypoxia. This hypoxia-mediated inhibition was reversed by NAC. Consistently, steroid hormone treatment had no significant effects on large conductance KCa current density in nonpregnant uterine arteries of hypoxic animals in the absence of NAC but significantly increased it in the presence of NAC. These results suggest an important role of hypoxia-mediated reactive oxygen species in negatively regulating steroid hormone-mediated upregulation of KCa channel activity and adaptation of uterine vascular reactivity in pregnancy, which may contribute to the increased incidence of preeclampsia and fetal intrauterine growth restriction associated with gestational hypoxia.

Dataset Information

Chronic hypoxia inhibits sex steroid hormone-mediated attenuation of ovine uterine arterial myogenic tone in pregnancy.

Publications

Chronic hypoxia inhibits sex steroid hormone-mediated attenuation of ovine uterine arterial myogenic tone in pregnancy.

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