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.
Chang
Katherine
K
Center for Perinatal Biology, Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
Xiao
DaLiao
D
Huang
Xiaohui
X
Xue
Zhice
Z
Yang
Shumei
S
Longo
Lawrence D
LD
Zhang
Lubo
L
D000818:Animals; D015153:Blotting, Western; D002908:Chronic Disease; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics; D047629:Estrogen Receptor beta / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D012739:Gonadal Steroid Hormones / Q000494:pharmacology*; D000860:Hypoxia / Q000503:physiopathology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology; D011980:Receptors, Progesterone / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012756:Sheep; D055988:Uterine Artery / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D014661:Vasoconstriction / Q000187:drug effects*
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D012739:Gonadal Steroid Hormones; D011980:Receptors, Progesterone; D011374:Progesterone; D004958:Estradiol; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3