title: 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 B-mediated inhibition of norepinephrine (NE)-induced contractions. Prolonged ex vivo treatment of NPUA with 17beta-estradiol and progesterone significantly attenuated PDBu-induced 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.
authors.affiliation: Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California 92350, USA. Dxiao@llu.edu
authors.forename: DaLiao
authors.initials: D
authors.lastname: Xiao
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Huang
authors.forename: Lubo
authors.initials: L
authors.lastname: Zhang
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D000532:Altitude Sickness / Q000503:physiopathology; D000818:Animals; D002140:California; D020536:Enzyme Activators / Q000494:pharmacology; D004958:Estradiol / Q000378:metabolism; D005260:Female; D000860:Hypoxia / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D058105:Polymerization / Q000187:drug effects; D011247:Pregnancy; D011248:Pregnancy Complications / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D011374:Progesterone / Q000378:metabolism; D011493:Protein Kinase C / Q000737:chemistry / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034561:Sheep, Domestic; D015854:Up-Regulation / Q000187:drug effects; D055988:Uterine Artery / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D020536:Enzyme Activators; D047428:Protein Kinase Inhibitors; D011374:Progesterone; D004958:Estradiol; D011493:Protein Kinase C; D009638:Norepinephrine