(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.
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