(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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD083132-03
Application #
9438916
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Loma Linda University
Department
Type
DUNS #
009656273
City
Loma Linda
State
CA
Country
United States
Zip Code
92350
Hu, Xiang-Qun; Dasgupta, Chiranjib; Chen, Man et al. (2017) Pregnancy Reprograms Large-Conductance Ca2+-Activated K+ Channel in Uterine Arteries: Roles of Ten-Eleven Translocation Methylcytosine Dioxygenase 1-Mediated Active Demethylation. Hypertension 69:1181-1191
Hu, Xiang-Qun; Zhang, Lubo (2017) Angiogenesis during pregnancy: all routes lead to MAPKs. J Physiol 595:4571-4572
Thorpe, Richard B; Hubbell, Margaret C; Silpanisong, Jinjutha et al. (2017) Chronic hypoxia attenuates the vasodilator efficacy of protein kinase G in fetal and adult ovine cerebral arteries. Am J Physiol Heart Circ Physiol 313:H207-H219
Shin, Alexandra N; Dasgupta, Chiranjib; Zhang, Guangyu et al. (2017) Proteomic Analysis of Endothelin-1 Targets in the Regulation of Cardiomyocyte Proliferation. Curr Top Med Chem 17:1788-1802
Silpanisong, Jinjutha; Kim, Dahlim; Williams, James M et al. (2017) Chronic hypoxia alters fetal cerebrovascular responses to endothelin-1. Am J Physiol Cell Physiol 313:C207-C218
Hu, Xiang-Qun; Dasgupta, Chiranjib; Xiao, Daliao et al. (2017) MicroRNA-210 Targets Ten-Eleven Translocation Methylcytosine Dioxygenase 1 and Suppresses Pregnancy-Mediated Adaptation of Large Conductance Ca2+-Activated K+ Channel Expression and Function in Ovine Uterine Arteries. Hypertension :
Mata-Greenwood, Eugenia; Goyal, Dipali; Goyal, Ravi (2017) Comparative and Experimental Studies on the Genes Altered by Chronic Hypoxia in Human Brain Microendothelial Cells. Front Physiol 8:365
Hu, Xiang-Qun; Chen, Man; Dasgupta, Chiranjib et al. (2017) Chronic hypoxia upregulates DNA methyltransferase and represses large conductance Ca2+-activated K+ channel function in ovine uterine arteries. Biol Reprod 96:424-434
Salehi, Arjang; Jullienne, Amandine; Baghchechi, Mohsen et al. (2017) Up-regulation of Wnt/?-catenin expression is accompanied with vascular repair after traumatic brain injury. J Cereb Blood Flow Metab :271678X17744124
Tenayuca, John; Cousins, Kimberley; Yang, Shumei et al. (2017) Computational Modeling Approach in Probing the Effects of Cytosine Methylation on the Transcription Factor Binding to DNA. Curr Top Med Chem 17:1778-1787

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