title: Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth.
abstract: Bradykinin-induced activation of the pulmonary endothelium triggers nitric oxide production and other signals that cause vasorelaxation, including stimulation of large-conductance Ca(2+)-activated K(+) (BKCa) channels in myocytes that hyperpolarize the plasma membrane and decrease intracellular Ca(2+). Intrauterine chronic hypoxia (CH) may reduce vasorelaxation in the fetal-to-newborn transition and contribute to pulmonary hypertension of the newborn. Thus we examined the effects of maturation and CH on the role of BKCa channels during bradykinin-induced vasorelaxation by examining endothelial Ca(2+) signals, wire myography, and Western immunoblots on pulmonary arteries isolated from near-term fetal (∼ 140 days gestation) and newborn, 10- to 20-day-old, sheep that lived in normoxia at 700 m or in CH at high altitude (3,801 m) for >100 days. CH enhanced bradykinin-induced relaxation of fetal vessels but decreased relaxation in newborns. Endothelial Ca(2+) responses decreased with maturation but increased with CH. Bradykinin-dependent relaxation was sensitive to 100 μM nitro-L-arginine methyl ester or 10 μM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, supporting roles for endothelial nitric oxide synthase and soluble guanylate cyclase activation. Indomethacin blocked relaxation in CH vessels, suggesting upregulation of PLA2 pathways. BKCa channel inhibition with 1 mM tetraethylammonium reduced bradykinin-induced vasorelaxation in the normoxic newborn and fetal CH vessels. Maturation reduced whole cell BKCa channel α1-subunit expression but increased β1-subunit expression. These results suggest that CH amplifies the contribution of BKCa channels to bradykinin-induced vasorelaxation in fetal sheep but stunts further development of this vasodilatory pathway in newborns. This involves complex changes in multiple components of the bradykinin-signaling axes.
authors.affiliation: Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California; Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, California;
authors.forename: Carla
authors.initials: C
authors.lastname: Blum-Johnston
authors.affiliation: Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California;
authors.forename: Richard B
authors.initials: RB
authors.lastname: Thorpe
authors.affiliation: Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California;
authors.forename: Chelsea
authors.initials: C
authors.lastname: Wee
authors.affiliation: Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California; Advanced Imaging and Microscopy Core, Loma Linda University School of Medicine, Loma Linda, California;
authors.forename: Monica
authors.initials: M
authors.lastname: Romero
authors.affiliation: Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California;
authors.forename: Alexander
authors.initials: A
authors.lastname: Brunelle
authors.affiliation: Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California;
authors.forename: Quintin
authors.initials: Q
authors.lastname: Blood
authors.affiliation: Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California; seanwilson@llu.edu.
authors.forename: Rachael
authors.initials: R
authors.lastname: Wilson
authors.affiliation: Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California; Division of Neonatology, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, California; and.
authors.forename: Arlin B
authors.initials: AB
authors.lastname: Blood
authors.affiliation: Department of Physiology and Cell Biology, University of South Alabama College of Medicine, Birmingham, Alabama.
authors.forename: Michael
authors.initials: M
authors.lastname: Francis
authors.affiliation: Department of Physiology and Cell Biology, University of South Alabama College of Medicine, Birmingham, Alabama.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Taylor
authors.affiliation: Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California;
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Longo
authors.affiliation: Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California;
authors.forename: William J
authors.initials: WJ
authors.lastname: Pearce
authors.affiliation: Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California; Advanced Imaging and Microscopy Core, Loma Linda University School of Medicine, Loma Linda, California;
authors.forename: Sean M
authors.initials: SM
authors.lastname: Wilson
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D001920:Bradykinin / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000254:growth & development / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011651:Pulmonary Artery / Q000254:growth & development / Q000378:metabolism; D012756:Sheep; D014664:Vasodilation / Q000502:physiology*
chemical_list: C026512:arginine methyl ester; D009569:Nitric Oxide; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; D001920:Bradykinin
keywords: contractility; hypoxia; maturation; potassium channels; pulmonary artery; sheep