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.
The investigations we propose help provide a mechanistic basis for the role of long-term intrauterine hypoxia in the development of pulmonary hypertension in the newborn. The goal of these studies is to associate ryanodine receptors with disease pathogenesis. Such results will provide an important positive impact, because ryanodine receptors are highly likely to provide novel targets for therapeutic interventions.
|Liu, Taiming; Schroeder, Hobe J; Wilson, Sean M et al. (2016) Local and systemic vasodilatory effects of low molecular weight S-nitrosothiols. Free Radic Biol Med 91:215-23|
|Ardekani, Soroush; Scott, Harry A; Gupta, Sharad et al. (2015) Nanoliposomal Nitroglycerin Exerts Potent Anti-Inflammatory Effects. Sci Rep 5:16258|
|Harraz, Osama F; Brett, Suzanne E; Zechariah, Anil et al. (2015) Genetic ablation of CaV3.2 channels enhances the arterial myogenic response by modulating the RyR-BKCa axis. Arterioscler Thromb Vasc Biol 35:1843-51|
|Harraz, Osama F; Abd El-Rahman, Rasha R; Bigdely-Shamloo, Kamran et al. (2014) Ca(V)3.2 channels and the induction of negative feedback in cerebral arteries. Circ Res 115:650-61|
|Zhu, Ronghui; Hu, Xiang-Qun; Xiao, Daliao et al. (2013) Chronic hypoxia inhibits pregnancy-induced upregulation of SKCa channel expression and function in uterine arteries. Hypertension 62:367-74|
|Papamatheakis, Demosthenes G; Blood, Arlin B; Kim, Joon H et al. (2013) Antenatal hypoxia and pulmonary vascular function and remodeling. Curr Vasc Pharmacol 11:616-40|
|Blood, Arlin B; Terry, Michael H; Merritt, Travis A et al. (2013) Effect of chronic perinatal hypoxia on the role of rho-kinase in pulmonary artery contraction in newborn lambs. Am J Physiol Regul Integr Comp Physiol 304:R136-46|
|Xiao, Daliao; Hu, Xiang-Qun; Huang, Xiaohui et al. (2013) Chronic hypoxia during gestation enhances uterine arterial myogenic tone via heightened oxidative stress. PLoS One 8:e73731|
|Hu, Xiang-Qun; Xiao, Daliao; Zhu, Ronghui et al. (2012) Chronic hypoxia suppresses pregnancy-induced upregulation of large-conductance Ca2+-activated K+ channel activity in uterine arteries. Hypertension 60:214-22|
|Hadley, Scott R; Blood, Quintin; Rubalcava, Monica et al. (2012) Maternal high-altitude hypoxia and suppression of ryanodine receptor-mediated Ca2+ sparks in fetal sheep pulmonary arterial myocytes. Am J Physiol Lung Cell Mol Physiol 303:L799-813|