Intrauterine chronic hypoxia and ryanodine receptors in fetal pulmonary arteries
Principal Investigator: Sean M Wilson
Abstract: DESCRIPTION (provided by applicant): Intrauterine stress can induce long-lived changes in function that predispose the fetus for disease throughout life. Maternal hypoxemia due to high altitude living, placental insufficiency, and smoking puts infants of certain populations at risk o developing pulmonary hypertension, high altitude pulmonary edema, and increases the risk for development of idiopathic pulmonary hypertension later in life. Gestation at high altitude causes a variety of pulmonary vascular malformations in fetal sheep including suppressed endothelium dependent relaxation, altered myocyte growth, and reactivity that place them at risk of developing hypertension after birth. Indeed, high altitude gestation and birth exaggerates hypoxia induced pulmonary vasoconstriction in 2 week old sheep and results in significant penetration of pulmonary hypertension. Sheep are therefore a relevant model for understanding novel pathways and mechanisms associated with fetal origins of pulmonary vascular disease because hypoxemia due to high altitude gestation recapitulates disease found in humans. The fundamental focus is that ryanodine receptors (RyR) are central to the process of pulmonary arterial constriction in response to acute alveolar hypoxia, which can be dysregulated in individuals with pulmonary hypertension. Three RyR isoforms are known, and all three are vital to the intrinsic vasoconstrictor response to acute hypoxia in pulmonary arteries. RyR channelopathies actively participate in the pathogenesis of neuronal, skeletal muscle, cardiac, and vascular diseases and yet their role in fetal programming of pulmonary vascular disease is unknown. The central hypothesis of this project is that high altitude gestation will suppress RyR-mediated local Ca2+ "sparks" and global Ca2+ responses due to acute hypoxia and that these responses will be manifested by reductions in RyR expression. We propose this counterbalances mechanisms that would increase vascular contraction to acute hypoxia. This would help reduce the extent of pulmonary hypertension due to long-term intrauterine hypoxia. The central hypothesis is based on published and preliminary studies performed with full-term fetal sheep. We plan to test our central hypothesis by pursuing two Specific Aims. Specific Aim 1 will determine whether high altitude gestation suppresses the expression of the three RyR isoforms. Specific Aim 2 will determine the corresponding reduction in RyR mediated Ca2+ responses and pulmonary vasoconstriction in response to acute hypoxia. The hypotheses will be examined by performing molecular, histochemical, and functional studies in pulmonary arteries from term-fetal lambs. With regards to the expected outcomes, the work proposed is expected to identify the influence of long-term intrauterine hypoxia on RyR function in the fetus. These studies are expected to fundamentally advance the field of pulmonary vascular biology by associating RyRs with pulmonary vascular disease. Such results will provide an important positive impact, because RyRs are highly likely to provide novel targets for therapeutic interventions in the treatment of pulmonary vascular disease.
Funding Period: 2012-06-01 - 2014-05-31
more information: NIH RePORT
- Chronic hypoxia suppresses pregnancy-induced upregulation of large-conductance Ca2+-activated K+ channel activity in uterine arteriesXiang Qun Hu
Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University, School of Medicine, Loma Linda, CA 92350, USA
Hypertension 60:214-22. 2012....
- Maternal high-altitude hypoxia and suppression of ryanodine receptor-mediated Ca2+ sparks in fetal sheep pulmonary arterial myocytesScott R Hadley
Center for Perinatal Biology, Loma Linda University, California 92350, USA
Am J Physiol Lung Cell Mol Physiol 303:L799-813. 2012..The influence of both ontogeny and LTH on RyR-dependent cell excitability shed new light on the therapeutic potential of these channels for the treatment of pulmonary vascular disease in newborns as well as adults...
- Effect of chronic perinatal hypoxia on the role of rho-kinase in pulmonary artery contraction in newborn lambsArlin B Blood
Department of Pediatrics, Division of Neonatology, Loma Linda University School of Medicine, Loma Linda, CA 92373, USA
Am J Physiol Regul Integr Comp Physiol 304:R136-46. 2013..We conclude that chronic hypoxia in utero results in increased vasopressor response to both acute hypoxia and serotonin, but that rho-kinase is involved only in the increased response to serotonin...
- Chronic hypoxia inhibits pregnancy-induced upregulation of SKCa channel expression and function in uterine arteriesRonghui Zhu
Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University, School of Medicine, Loma Linda, CA 92350, USA
Hypertension 62:367-74. 2013..The findings suggest a novel mechanism of SKCa channels in regulating myogenic adaptation of uterine arteries in pregnancy and in the maladaptation of uteroplacental circulation caused by chronic hypoxia during gestation...
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Center for Perinatal Biology, Loma Linda University School of Medicine, 11234 Anderson Street, Loma Linda, 92350 CA, USA
Curr Vasc Pharmacol 11:616-40. 2013....
- Chronic hypoxia during gestation enhances uterine arterial myogenic tone via heightened oxidative stressDaliao Xiao
Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, United States of America
PLoS ONE 8:e73731. 2013....
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