Preeclampsia-Induced Fetal Endothelial Dysfunction in Obese Pregnancy: Novel roles of miR192-5p

肥胖妊娠中子痫前期诱发的胎儿内皮功能障碍：miR192-5p 的新作用

• 批准号: 10259928
• 负责人: CHI ZHOU
• 金额: $ 7.68万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10259928
• 关键词: Adult; Birth; Blood; Blood Circulation; Blood Vessels; Body mass index; Cardiovascular Diseases; Cardiovascular system; Cell Proliferation; Cell model; Cells; Child; Data; Developed Countries; Disease; Endothelial Cells; Endothelium; Exhibits; Face; Female; Fetus; Genes; Growth Factor; Hormones; Human; Hypertension; Impairment; Inflammation; Inflammatory; Life; Link; Longitudinal Studies; Maternal Mortality; MicroRNAs; Modeling; Obesity; Outcome; Phenotype; Placenta; Play; Pre-Eclampsia; Pregnancy; Prevention; Regulation; Reporting; Research; Risk; Risk Factors; Role; Signal Pathway; Study models; System; TNF gene; Testing; Thinness; Umbilical vein; Vascular Endothelial Cell; Vascular Endothelium; Western Blotting; Woman; cardiovascular disorder risk; cardiovascular risk factor; cell growth; cell motility; cytokine; endothelial dysfunction; fetal; human male; in utero; knock-down; male; maternal morbidity; maternal obesity; migration; monolayer; new therapeutic target; novel; novel marker; nutrition; obese mothers; overexpression; programs; response; risk prediction; sex

PROJECT SUMMARY / ABSTRACT Preeclampsia (PE) is a hypertensive disorder and one of the leading causes of fetal/maternal morbidity and mortality during pregnancy. PE is characterized by impaired fetal and maternal endothelial function and excessive inflammation. Children born to PE will face increased risks of cardiovascular disorders later in life, suggesting that PE programs fetal vascular cells in utero. To date, the mechanisms underlying PE-associated fetal endothelial dysfunction remain elusive. Maternal obesity is one of the prevalent risk factors that associated with PE in developed countries. Maternal obesity increases the overall risk of PE by 3 fold. Children born to obese mother also exhibit higher blood pressure and increased risks of adverse cardiovascular outcomes in adulthood. Elevated TNFα and TGFβ1 levels are associated with endothelial dysfunction in PE. Compared with lean subjects, obese women have increased pro-inflammatory cytokines (e.g. TNFα) levels in placenta and increased TGFβ1 levels in maternal circulation. Human umbilical vein is the blood vessel transporting all nutrition, O2, and other humoral factors (e.g. cytokines) from the placenta and maternal system into the fetus. Hence, human umbilical vein endothelial cells (HUVECs) is widely used as a human fetal endothelial cell model. MiR192- 5p is a cardiovascular diseases-associated microRNA which regulates endothelial cell growth in cultured HUVECs. Our preliminary data have shown that increased miR192-5p expression inhibits the TNFα- and TGFβ1-induced cell migration in HUVECs. We and others have reported that PE decreases miR192 expression in freshly isolated and unpassaged (P0)-HUVECs and in placentas. Our data further demonstrated that i) PE downregulated miR192-5p in male but not in female P0-HUVECs from lean pregnancies; ii) PE upregulated miR192-5p in both female and male P0-HUVECs from obese pregnancies; and iii) Male P1-HUVECs from lean PE exhibit weaker responses (monolayer integrity) to TNFα and TGF-β1 than female cells did. As TNFα and TGFβ1 are both upstream regulators of miR192- 5p, these data suggest that miR192-5p plays an important and differential role in TNFα and/or TGFβ1- regulated fetal endothelial function in lean and obese PE. Overall hypothesis: PE programs fetal endothelial cells by dysregulating endothelial function-associated microRNAs and their target genes, leading to fetal endothelial dysfunction, and ultimately laying the groundwork for adult onset cardiovascular disorders in children born to PE. Specifically, in this application, I will test the hypothesis that miR192-5p differentially regulates the PE-induced fetal endothelial dysfunction in lean and obese pregnancies via the TNFα and/or TGFβ1 signaling pathways using HUVECs as a model. Results from our proposed studies will advance our understanding of the roles of miRNAs in PE-induced fetal sex- specific endothelial dysfunction in lean and obese pregnancies. In the long term, these studies may reveal novel biomarkers or therapeutic targets for fetal sex-specific cardiovascular risk prediction, treatment, and even prevention in children born to lean and obese PE.

项目摘要/摘要 子痫前期(PE)是一种高血压疾病，是导致胎儿/母体疾病的主要原因之一 妊娠期发病率和死亡率。PE的特点是胎儿和母亲的内皮细胞受损 功能和过度炎症。出生于PE的儿童将面临更高的心血管风险 在生命后期的紊乱，表明PE在子宫中对胎儿血管细胞进行编程。到目前为止，这些机制 潜在的PE相关的胎儿内皮功能障碍仍然难以捉摸。产妇肥胖症是 发达国家普遍存在的与PE相关的危险因素。母亲肥胖增加了 PE的总体风险增加3倍。肥胖母亲所生的孩子也表现出更高的血压和 成年后心血管不良结局的风险增加。升高的肿瘤坏死因子α和转化生长因子β1水平是 与PE的内皮功能障碍有关。与苗条的受试者相比，肥胖女性 胎盘中促炎症细胞因子(如肿瘤坏死因子α)水平升高和转化生长因子β1水平升高 母体循环。人的脐静脉是输送所有营养、氧气和其他物质的血管 体液因子(如细胞因子)从胎盘和母体系统进入胎儿。因此，人类 脐静脉内皮细胞(HUVECs)是目前广泛使用的人胎儿血管内皮细胞模型。MiR192- 5P是一种与心血管疾病相关的微RNA，调节培养的血管内皮细胞生长 HUVEC。我们的初步数据显示，miR192-5p表达增加抑制了肿瘤坏死因子α-和 转化生长因子β1诱导人脐静脉内皮细胞迁移。我们和其他人报告说，市盈率下降了192 在新鲜分离的和未传代的(P0)人脐静脉内皮细胞和胎盘中的表达。我们的数据进一步 结果表明：1)PE使男性P0-HUVECs的miR192-5p表达下调，但对雌性P0-HUVECs的miR192-5p表达无影响 怀孕；ii)肥胖的P0-HUVECs中PE上调女性和男性P0-HUVECs的miR192-5p III)来自瘦肉型PE的雄性P1-HUVECs对 肿瘤坏死因子α和转化生长因子β1的表达高于雌性细胞。由于肿瘤坏死因子α和转化生长因子β1都是miR192的上游调控因子- 这些数据表明，miR192-5p在肿瘤坏死因子α和/或转化生长因子β1中起着重要的和不同的作用。 瘦肉型和肥胖型PE胎儿内皮功能的调节总体假设：体育项目为胎儿 内皮细胞通过失调内皮功能相关的microRNA及其靶基因， 导致胎儿内皮功能障碍，最终为成人发病奠定基础 出生于体育的儿童的心血管疾病。具体地说，在这个应用程序中，我将测试假设 MiR192-5p对瘦体和肥胖者PE诱导的胎儿内皮功能障碍的差异性调节 以人脐静脉内皮细胞为模型，通过肿瘤坏死因子α和/或转化生长因子β1信号通路进行妊娠。结果来自 我们提出的研究将促进我们对miRNAs在PE诱导的胎儿性行为中的作用的理解。 瘦身和肥胖孕妇的特异性内皮功能障碍。从长远来看，这些研究可能会揭示 新的生物标志物或治疗靶点用于胎儿性别特异性心血管风险预测、治疗、 甚至预防出生时身体偏瘦和肥胖的孩子。