Long-term effects of prenatal hypoxia on endothelium-dependent relaxation responses in pulmonary arteries of adult sheep.
Chronic hypoxia during the course of pregnancy is a common insult to the fetus. However, its long-term effect on the pulmonary vasculature in adulthood has not been described. In this study, the vasorelaxation responses of conduit pulmonary arteries in adult female sheep that were chronically hypoxic as fetuses and raised postnatally at sea level were investigated. Vessel tension studies revealed that endothelium-dependent relaxation responses were attenuated in pulmonary arteries from adult sheep that experienced prenatal hypoxia. Endothelial nitric oxide synthase (eNOS) protein expression was unchanged, but eNOS activity was significantly decreased in pulmonary arteries from prenatally hypoxic sheep. Protein expression of eNOS partners, caveolin-1, calmodulin, and heat shock protein 90 (Hsp90) did not change following prenatal hypoxia. However, the association between eNOS and caveolin-1, its inhibitory binding partner, was significantly increased, whereas association between eNOS and its stimulatory partners calmodulin and Hsp90 was greatly decreased. Furthermore, phosphorylation of Ser(1177) in eNOS decreased, whereas phosphorylation of Thr(495) increased, in the prenatally hypoxic pulmonary arteries, events that are related to eNOS activity. These data demonstrate that prenatal hypoxia results in persistent abnormalities in endothelium-dependent relaxation responses of pulmonary arteries in adult sheep due to decreased eNOS activity resulting from altered posttranslational regulation.
Liu
Jie
J
Division of Neonatology, Harbor-University of California, Los Angeles Medical Center, Geffen School of Medicine at University of California, and Los Angeles Biomedical Research Institute, Los Angeles, California 90502, USA. jliu@labiomed.org
Gao
Yuansheng
Y
Negash
Sewite
S
Longo
Lawrence D
LD
Raj
J Usha
JU
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002147:Calmodulin / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000503:physiopathology; D005260:Female; D005311:Fetal Hypoxia / Q000503:physiopathology*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D052250:Nitric Oxide Synthase Type III / Q000737:chemistry / Q000378:metabolism; D009603:Nitroso Compounds / Q000494:pharmacology; D010766:Phosphorylation; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology*; D012694:Serine / Q000737:chemistry; D012756:Sheep; D013912:Threonine / Q000737:chemistry; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D002147:Calmodulin; D051242:Caveolin 1; D018841:HSP90 Heat-Shock Proteins; D009603:Nitroso Compounds; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D013912:Threonine; D000001:Calcimycin; D012694:Serine; D052250:Nitric Oxide Synthase Type III; D000109:Acetylcholine