Myometrial artery potassium channel activity in intrauterine growth restriction pregnancy

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PROJECT SUMMARY Intrauterine growth restriction (IUGR) increases the risk of stillbirth and neonatal death. The adverse effects of being born IUGR extend well beyond the perinatal period, increasing the risk of cardiovascular disease, among others, in later life. Currently, no effective strategies exist to prevent or treat IUGR. Our overarching goal is to determine the role of K+ channels and intracellular Ca2+ in the regulation of myometrial artery vasoreactivity, both important contributors to uteroplacental perfusion, and, in turn, fetal growth. We expect that two of the most prevalent K + channels in uterine vasculature, BK Ca and K ATP channels, will be impaired in IUGR pregnancy, in association with reduced MA vasorelaxation and fetal growth. To address this goal, we propose to conduct two integrated scientific aims. In Aim 1, we will determine whether (1) the vasodilatory role of BKCa and/or KATP channels is diminished in myometrial arteries from IUGR pregnancies compared to uncomplicated pregnancies; (2) K+ currents mediated by BKCa and/or KATP channels are reduced in myometrial artery smooth muscle cells from IUGR compared to uncomplicated pregnancies; and (3) IUGR impairs the protein expression and/or localization of these channels in myometrial arteries and placenta. Aim 2 will address the role of store- operated Ca2+ entry and intracellular Ca2+ stores in myometrial arteries from IUGR by asking whether myometrial artery smooth muscle cells from IUGR pregnancies show dysregulated store-operated Ca2+ entry and/or intracellular Ca2+ stores. Participants will be women with uncomplicated or IUGR pregnancies. Scientifically, the work proposed is vital to improving our understanding of the mechanisms underlying the reduced uteroplacental blood flow observed in IUGR pregnancies. Our proposed project also has potentially important clinical implications; in particular, our study outcomes may identify novel therapeutic targets to treat or prevent IUGR.