(Project I) The striking increase of uterine blood flow during pregnancy is essential both for optimal growth of the fetus and cardiovascular well-being of the mother. Maladaptation of the uteroplacental circulation during gestation is associated with high incidence of clinical complications including preeclampsia and fetal intrauterine growth restriction. Large-conductance Ca2+-activated K+ (BKca) channels play a critical role in regulating uterine blood flow in pregnancy. Recent studies in sheep demonstrated that pregnancy and steroid hormones caused a significant increase in BKCa ?1 subunit resulting in increased ?1:? subunit stoichiometry and heightened BKCa channel activity in uterine arteries. Chronic hypoxia during gestation abrogated these changes. Yet the molecular mechanisms remain unknown. Our preliminary studies showed that pregnancy and steroid hormones caused a decrease in DNA methylation at the ?1 gene promoter. DNA methylation is a chief mechanism in epigenetic repression of gene expression patterns, and recent studies suggest a robust mechanism of ten-eleven translocation 1-3 (TET1-3) proteins in active DNA demethylation. Preliminary studies suggested that pregnancy and steroid hormones increased TET1-2 expression in uterine arteries. These findings lead to the proposed studies of a highly novel mechanism testing the hypothesis that steroid hormone-induced, epigenetic-mediated dynamic changes of DNA methylation and demethylation play a key role in regulating expression and function of BKca channels in uterine vascular adaptation to pregnancy and chronic hypoxia.
Three specific aims will determine whether: 1) steroid hormone-mediated promoter demethylation and BKca ?1 gene up-regulation play a causal role in increased BKca channel function in uterine arteries in pregnancy, 2) steroid hormones increase the expression of TET1-3 proteins in uterine arteries, and 3) steroid hormone-mediated up-regulation of TET1-3 plays a causal role in active DNA demethylation and the ?1 gene reactivation in pregnancy. The results will significantly advance our knowledge in molecular mechanisms of uteroplacental adaptation to pregnancy and improve our understanding of pathophysiological mechanisms underlying maladaptation of uteroplacental circulation and pregnancy complications associated with chronic hypoxia. They will also have a broad impact in understanding of molecular mechanisms in regulating BKca channel activity and vascular function in physiology and pathophysiology.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Loma Linda University
Loma Linda
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Ducsay, Charles A; Goyal, Ravi; Pearce, William J et al. (2018) Gestational Hypoxia and Developmental Plasticity. Physiol Rev 98:1241-1334
Goyal, Dipali; Goyal, Ravi (2018) Developmental Maturation and Alpha-1 Adrenergic Receptors-Mediated Gene Expression Changes in Ovine Middle Cerebral Arteries. Sci Rep 8:1772
Liu, Taiming; Zhang, Meijuan; Terry, Michael H et al. (2018) Hemodynamic Effects of Glutathione-Liganded Binuclear Dinitrosyl Iron Complex: Evidence for Nitroxyl Generation and Modulation by Plasma Albumin. Mol Pharmacol 93:427-437
Manaenko, Anatol; Yang, Peng; Nowrangi, Derek et al. (2018) Inhibition of stress fiber formation preserves blood-brain barrier after intracerebral hemorrhage in mice. J Cereb Blood Flow Metab 38:87-102
Wan, Weifeng; Ding, Yan; Xie, Zongyi et al. (2018) PDGFR-? modulates vascular smooth muscle cell phenotype via IRF-9/SIRT-1/NF-?B pathway in subarachnoid hemorrhage rats. J Cereb Blood Flow Metab :271678X18760954
Hu, Xiang-Qun; Dasgupta, Chiranjib; Xiao, Jeffery et al. (2018) Long-term high altitude hypoxia during gestation suppresses large conductance Ca2+ -activated K+ channel function in uterine arteries: a causal role for microRNA-210. J Physiol 596:5891-5906
Hays, Tristan T; Ma, Ben; Zhou, Ning et al. (2018) Vascular smooth muscle cells direct extracellular dysregulation in aortic stiffening of hypertensive rats. Aging Cell 17:e12748
Liu, Taiming; Zhang, Meijuan; Terry, Michael H et al. (2018) Nitrite potentiates the vasodilatory signaling of S-nitrosothiols. Nitric Oxide 75:60-69
Pearce, William J (2018) For myosin light chain phosphatase, a very small subunit can make very big differences in the heart. Am J Physiol Heart Circ Physiol 314:H1157-H1159
Blum-Johnston, Carla; Thorpe, Richard B; Wee, Chelsea et al. (2018) Long-term hypoxia uncouples Ca2+ and eNOS in bradykinin-mediated pulmonary arterial relaxation. Am J Physiol Regul Integr Comp Physiol 314:R870-R882

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