Uterine blood flow increases significantly during pregnancy, which 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. The BKca channel in vascular smooth muscle contains the channel-forming ? subunit and up to four accessory ?1 subunits that enhance the Ca2+ sensitivity of BKca channels. Previous 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. Of importance, chronic hypoxia during gestation abrogated these changes. Yet the molecular mechanisms remain unknown. Our recent study 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. Our preliminary studies suggested that pregnancy and steroid hormones increased TET1-2 expression in uterine arteries. Furthermore, the preliminary data demonstrated that chronic hypoxia during gestation resulted in a significant increase in microRNA 210 (miR210) in uterine arteries, which targeted TET1 mRNA 3'UTR and negatively regulated its translation. With these exciting findings and many highly novel leads, we are positioned to move the field forward significantly in a manner by launching a new and paradigm-shifting focus of research and to test the hypothesis that molecular and epigenetic mechanisms of miR210 interacting with TET-mediated DNA 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 hormones upregulate TET gene expression leading to DNA demethylation and increased BKca ?1 gene expression in uterine arterial adaptation to pregnancy, 2) chronic hypoxia during gestation increases miR210 inhibiting TET mRNA translation and abrogates steroid hormone-mediated upregulation of BKca ?1 gene expression in uterine arteries, and 3) determine the causal effect of miR210 and TET-mediated demethylation in regulating BKca channel function in uterine arterial adaptation to pregnancy and hypoxia. 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 the uteroplacental circulation and pregnancy complications associated with chronic hypoxia. They also will have a broad impact in the understanding of molecular mechanisms in regulating BKca channel activity and vascular function in general in physiology and pathophysiology.
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 in pregnancy is associated with high incidence of clinical complications including preeclampsia and fetal intrauterine growth restriction. The proposed study will provide new insights into the molecular mechanisms underlying aberrant uteroplacental circulation caused by hypoxia during gestation and suggest new directions in the clinical management of pregnancy complications associated with hypoxia, thereby reducing perinatal morbidity while improving maternal health and neonatal outcome.
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