Role of E2B Metabolites in Uterine Artery Endothelial Adaptations to Pregnancy

E2B 代谢物在子宫动脉内皮适应妊娠中的作用

基本信息

批准号：
9126810
负责人：
ROSALINA VILLALON LANDEROS
金额：
$ 3.61万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9126810
关键词：
2-methoxyestradiol Adult Affect Area Arteries Barker Hypothesis Biological Assay Birth Weight Blood Circulation Blood Vessels Blood flow CELSR1 gene Cardiovascular Diseases Cell Cycle Cell Proliferation Centers for Disease Control and Prevention (U.S.)Contralateral Development Disease Doctor of Philosophy Educational process of instructing Endothelial Cells Endothelium Environment Epoprostenol Estradiol Exhibits Fetal Development Fetal Growth Fetal Growth Retardation Fetus Funding Goals Grant Health Healthcare Systems High Pressure Liquid Chromatography Hormonal Hormones Horns Hypertension Immunoassay Incidence Ipsilateral Knowledge Laboratories Lead Leadership Link Manuscripts Mentorship Modeling Modification Neonatal Mortality Nitric Oxide Non-Insulin-Dependent Diabetes Mellitus Nutrient Onset of illness Operative Surgical Procedures Oxygen Pathologic Patient currently pregnant Perinatal mortality demographics Phosphorylation Play Positioning Attribute Postdoctoral Fellow Pre-Eclampsia Pregnancy Preventive Production Prostaglandins I Research Research Personnel Role Sheep Signal Transduction Training United States National Institutes of Health Vasodilation Vasodilator Agents Writing angiogenesis career career networking cost estrogenic experience fetal high risk improved innovation neonatal morbidity perinatal morbidity pregnancy disorder pregnant prevent programs public health relevance

项目摘要

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 (E2β) 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 E2β 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.

描述（由应用程序提供）：此F31多样性应用程序为Rosalina Villalon Landeros提供了详细的培训计划，以实现她完成的职业职业目标她的博士学位，过渡到高水平的博士后职位，并成为独立的研究人员。她的培训计划确定了心态和培训领域，例如：写作手稿和赠款，2）专业网络，3）教学/指导和领导才能。她的科学项目由她的赞助商（RR Magness）NIH授予5P01HD038843-12和其他NIH赠款与子宫艺术适应怀孕以及直接局部环境的作用相关的NIH赠款，而与全身性马匹在此类适应中的作用有关。子宫动脉内皮细胞（UAECS）在子宫血管适应的机制中起着核心作用，包括血管生成和血管舒张，这对于增加正常妊娠期间子宫血流（UBF）是必不可少的。由于子宫异常的血管适应导致胎儿改善的胎儿，导致胎儿循环不足生长，最终在内部生长限制（IUGR）中。已知雌二醇（E2β）及其代谢产物，即catecolestradiols 2-OHE2和4-HOHE2以及替氧雌二醇2-ME2和4-ME2，通过增加UAEC增殖，前列腺酸蛋白和硝酸产生的生产而增加了孕妇在正常怀孕期间的子宫动脉功能，从而调节子宫动脉功能。我们的实验室开发了独特的卵巢外科手术诱导的单侧妊娠模型，通过该模型，与对侧动脉相比，子宫动脉的同侧是妊娠角的同侧进行大量重塑。该模型将使我们能够将局部妊娠环境与全身性角环境的影响进行比较对子宫动脉适应和内皮细胞编程的影响。 The overall hypothesis is that uterine arteries ipsilateral and contralateral to the gravid horn will exist 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 pregnancy, while UAECs isolated from uterine arteries与妊娠p-uaecs（Nongravid）P-uaecs相对的对比，将表现出与循环母羊NP-UAEEC相同的编程（低血管生成和血管扩张剂的产生）。（at）P-UAEC，（Nongravid）P-UAEC和P-UAECS NP-UAEEC，以前从具有或没有子宫手术修饰的健康母羊中分离出来并验证。 E2β及其代谢产物刺激的，与正常和非孕期相比，将通过检查（通过增殖测定法）和血管舒张剂的产生（通过免疫测定和HPLC）来确定静脉角的编程差异（通过增殖测定）和血管舒张剂的产生（通过免疫测定和HPLC）来确定。这些研究将促进我们对妊娠子宫血管适应的理解，并为未来的研究提供了平台，旨在识别当地急性环境中分泌的因素，这可能会导致对IUGR和先兆子痫的预防或纠正疗法的创新。