Role of E2B Metabolites in Uterine Artery Endothelial Adaptations to Pregnancy

University Of Wisconsin-Madison, Madison WI

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Abstract

? DESCRIPTION (provided by applicant): This F31-Diversity application provides a detailed training plan for Rosalina Villalon Landeros to fulfill her professional career goals of completing her PhD degree, transition into a high level postdoc position, and become an independent researcher. Her training plan identifies areas of mentorship and training such as: writing manuscripts and grants, 2) professional networking, 3) Teaching/Mentorship and leadership. Her scientific project is funded by her sponsor's (RR Magness) NIH grant 5P01HD038843-12 and other NIH grants that relate to uterine artery adaptations to pregnancy and the role of the immediate local environment versus the systemic hormonal profile on such adaptations. Uterine artery endothelial cells (UAECs) play a central role in the mechanisms underlying uterine vascular adaptations, including angiogenesis and vasodilatation, which are necessary to increase uterine blood flow (UBF) during normal pregnancy. Inadequate maternal-fetal circulation as a result of aberrant utero-placental vascular adaptations results in decreased fetal growth and ultimately in intrauterine growth restriction (IUGR). Estradiol (E2?) and its metabolites, the catecholestradiols 2-OHE2 and 4-OHE2 and the methoxyestradiols 2-ME2 and 4-ME2, are known to regulate uterine artery function during normal pregnancy by increasing UAEC proliferation, prostacyclin and nitric oxide production resulting in increased angiogenesis and vasodilatation. Our laboratory developed a unique ovine surgical-induced unilateral pregnancy model, through which we have found that uterine arteries ipsilateral to the gravid horn undergo substantial remodeling compared to contralateral arteries. This model will allow us to compare the effects of the local gravid environment to the systemic hormonal milieu on uterine artery adaptation and endothelial cell programming. The overall hypothesis is that uterine arteries ipsilateral and contralateral to the gravid horn will exhibit differences in programming so that UAECs isolated from uterine arteries ipsilateral to the gravid horn [(Gravid)P-UAECs] will exhibit the same programming (increased angiogenesis and vasodilation) as P-UAECs of normal pregnancies, while UAECs isolated from uterine arteries contralateral to the gravid horn [(NonGravid)P-UAECs] will exhibit the same programing (lower angiogenesis and vasodilator production) as NP-UAECs of cycling ewes. (Gravid)P-UAECs, (NonGravid)P- UAECs, and P-UAECs NP-UAECs, previously isolated and validated from healthy ewes with or without uterine surgical modification will be used. Differences in programming of UAECs ipsilateral and contralateral to the gravid horn will be determined by examining angiogenesis (through proliferation assays) and vasodilator production (through immunoassays and HPLC) stimulated by E2? and its metabolites and in comparison to normal and nonpregnancy. These studies will advance our understanding of uterine vascular adaptations to pregnancy and set the platform for future research aimed at identifying factors secreted in the local gravid milieu which may lead to the innovation of preventive or corrective treatments for IUGR and preeclampsia.