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This Article Full Text Full Text (PDF) All Versions of this Article: 296/3/L547    most recent 90333.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Liu, J. Articles by Raj, J. U. Search for Related Content PubMed PubMed Citation Articles by Liu, J. Articles by Raj, J. U.

Long-term effects of prenatal hypoxia on endothelium-dependent relaxation responses in pulmonary arteries of adult sheep

¹Division 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; and ²Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California

Submitted 3 June 2008 ; accepted in final form 5 January 2009

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 Ser¹¹⁷⁷ in eNOS decreased, whereas phosphorylation of Thr⁴⁹⁵ 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.

endothelial nitric oxide synthase; caveolin-1; calmodulin; heat shock protein 90