Submitted on June 3, 2008
Revised on December 10, 2008
Accepted on January 5, 2009
Long-term effects of prenatal hypoxia on endothelium-dependent relaxation responses in pulmonary arteries of adult sheep
Jie Liu1*, Yuansheng Gao2, Sewite Negash2, Lawrence D. Longo3, and J. Usha Raj2
1 Division of Neonatology, Harbor-UCLA Medical Center, Geffen School of Medicine at University of California, and Los Angeles Biomedical Research Institute, Los Angeles, California
2 Harbor-UCLA Medical Center
3 Loma Linda University School of Medicine
* To whom correspondence should be addressed. E-mail: jliu{at}labiomed.org.
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 pulmonary arteries in adult sheep that were chronically hypoxic as fetuses and raised post-natally 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, while association between eNOS and its stimulatory partners calmodulin and Hsp90 was greatly decreased. Furthermore, phosphorylation of Ser1177 in eNOS decreased, while 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.
