Chronic hypoxia differentially up-regulates protein kinase C-mediated ovine uterine arterial contraction via actin polymerization signaling in pregnancy

Abstract

Chronic hypoxia (CH) during pregnancy is associated with increased uterine vascular tone. The present study tested the hypothesis that CH up-regulates protein kinase C (PKC)- mediated actin polymerization, resulting in enhanced uterine vascular contraction in pregnancy. Uterine arteries were isolated from nonpregnant (NPUA) and near-term (~140 days of gestation) pregnant (PUA) sheep that had been maintained at sea level (~300 m) or exposed to high altitude (3801 m) hypoxia for 110 days. In normoxic animals, the induced contractions by the PKC activator phorbol 12,13-dibutyrate (PDBu) were greater in NPUA than in PUA, which was abrogated by an actin polymerization inhibitor cytochalasin B (Cyto B). In hypoxic animals, PDBu-induced contractions were significantly increased in PUA but not in NPUA, which was inhibited by Cyto B. In contrast, neither pregnancy nor hypoxia affected Cyto Bmediated inhibition of norepinephrine (NE)-induced contractions. Prolonged ex vivo treatment of NPUA with 17betaestradiol and progesterone significantly attenuated PDBuinduced actin polymerization and contractions, and the hormonal treatment did not alter the inhibitory effect of Cyto B on PDBu- or NE-induced contractions in either normoxic or hypoxic animals. 2-(2-Amino-3-methoxyphenyl)-4H-1-benzopyran- 4-one potentiated PDBu-mediated actin polymerization and enhanced PDBu-induced contractions of PUA in normoxic but not hypoxic animals, which was abrogated by Cyto B. The results suggest that chronic hypoxia during pregnancy causes attenuation of steroid hormone-mediated ERK1/2 signaling and results in increased actin polymerization and uterine vascular tone, linking gestational hypoxia to aberrant uteroplacental circulation. © 2012 by the Society for the Study of Reproduction, Inc.