Effect of obesity on antiangiogenic and inflammatory mechanisms mediating hypertension during pregnancy

肥胖对介导妊娠期高血压的抗血管生成和炎症机制的影响

• 批准号: 9014041
• 负责人: Frank Travis Spradley
• 金额: $ 8.92万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-19 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9014041
• 关键词: Adoptive Transfer; Affect; Age; Angiogenesis Inhibitors; Angiogenic Factor; B-Lymphocytes; Blood Circulation; Blood Pressure; Blood Vessels; Brain Hypoxia-Ischemia; CD4 Positive T Lymphocytes; Cells; Cessation of life; Chronic; Complex; Data; Development; Disease; Endothelin-1; Endothelium; Excretory function; Fetal Death; Flow Cytometry; Goals; Grant; Helper-Inducer T-Lymphocyte; Human; Hypertension; Hypoxia; Immune; Immune response; Incidence; Inflammatory; Inflammatory Response; Infusion procedures; Ischemia; Kidney; Laboratories; Learning; Leptin; Link; Mediating; Melanocortin 4 Receptor; Mentors; Metabolic; Modeling; Obesity; Overweight; Pathway interactions; Perfusion; Phase; Placenta; Placental Growth Factor; Placentation; Plasma; Population; Pre-Eclampsia; Pregnancy; Pregnant Women; Premature Birth; Prevalence; Production; Protein Tyrosine Kinase; Rattus; Reporting; Risk; Risk Factors; Signal Transduction; Stimulus; T-Lymphocyte; TNF gene; Techniques; Testing; Vascular Endothelial Growth Factors; Weight; Woman; effective therapy; hemodynamics; human data; insight; maternal hypertension; maternal morbidity; novel; perinatal morbidity; pregnant; pressure; receptor; reproductive; research study; response; therapeutic development; transcription factor

 DESCRIPTION (provided by applicant): The incidence of preeclampsia (PE), a complex disorder of new-onset hypertension during pregnancy, is on the rise calling for studies examining how the increasing prevalence of risk factors like obesity exaggerates the mechanisms that promote this hypertension. Although human studies have consistently shown a positive association between obesity and PE, there are no mechanistic studies to speak of. Insight into such mechanisms comes from classical studies showing that placental ischemia in pregnant rats results in the release of antiangiogenic factors such as soluble fms-like 1 tyrosine kinase (sFlt-1) from the placenta, mediated by the transcription factor HIF-1α, into the maternal circulation where it antagonizes placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) to elicit increased renal endothelin-1 (ET-1) then hypertension. Human data highlight a possible connection between sFlt-1 and the obesity-related metabolic factor leptin to greater hypertension in obese PE women. Therefore, the central hypothesis for my K99 is that obesity and leptin amplify placental ischemia-induced production of sFlt-1 via a HIF-1α-dependent mechanism, which mediates an exaggerated blood pressure response via ET-1 with specific aims testing hypotheses that: 1) obesity and leptin enhance hypoxia and/or placental ischemia-induced increases placental production of sFlt-1 in a HIF-1α-dependent mechanism, and 2) obesity and leptin exacerbate the blood pressure and renal hemodynamics to placental ischemia or chronic sFlt-1 excess via ET-1 signaling. The rationale for my R00 phase is that placental ischemia elicits a pro-inflammatory response with activation of maternal CD4+ T lymphocyte cells, which release TNFα and promotes B cells to secrete AT1-AA. Each of these factors causes hypertension when infused into normal pregnant rats via ET-1. As human data have hinted that these inflammatory factors are exaggerated in obese PE pregnancies, the central hypothesis of my R00 is that obesity and leptin can exaggerate the development of placental ischemia-induced hypertension via immune mechanisms with specific aims testing the hypotheses that: 3) obesity and chronic leptin excess enhance placental ischemia-induced increases in CD4+ T helper resulting in exaggerated hypertension and renal ET-1 responses mediated by TNFα, and 4) obesity and chronic leptin excess enhance placental ischemia-induced increases in B cells resulting in exaggerated hypertension and renal ET-1 responses mediated by AT1-AA. I have strong preliminary data to support my hypotheses using a unique obese pregnant rat model (melanocortin-4 receptor-deficient rats), which I will plan to combine with techniques that I have learned to induce placental ischemia in the rat and those that I plan to learn such as adoptive transfer of immune cells and flow cytometry to test my hypotheses in this proposal. Thus, my goal is to identify the pathways whereby obesity amplifies the risk for PE by examining the mechanisms linking placental ischemia to hypertension. The hope is that these studies aid in the development of therapeutic strategies to circumvent the development PE.

 描述（由申请人提供）：先兆子痫（PE）是妊娠期间新发高血压的一种复杂疾病，其发病率正在上升，需要研究肥胖等风险因素的日益普遍如何夸大促进这种高血压的机制。虽然人类研究一直显示肥胖和PE之间存在正相关，但没有机制研究。对这些机制的了解来自经典研究，这些研究表明，妊娠大鼠的胎盘缺血导致抗血管生成因子如可溶性fms样1酪氨酸激酶（sFlt-1）从胎盘释放，由转录因子HIF-1α介导，进入母体循环，在那里它拮抗胎盘生长因子（PlGF）和血管内皮生长因子（VEGF），引起肾内皮素-1（ET-1）然后是高血压。人类数据突出了sFlt-1和肥胖相关代谢因子瘦素与肥胖PE女性中更高的高血压之间的可能联系。因此，我的K99的中心假设是肥胖和瘦素通过HIF-1α依赖性机制放大胎盘缺血诱导的sFlt-1的产生，其通过ET-1介导夸大的血压反应，具体目的是测试假设：1）肥胖和瘦素在HIF-1α依赖性机制中增强缺氧和/或胎盘缺血诱导的sFlt-1的胎盘产生增加，肥胖和瘦素通过ET-1信号途径加重血压和肾血流动力学，导致胎盘缺血或sFlt-1慢性过量。我的R 00阶段的基本原理是胎盘缺血激发了促炎反应，激活了母体CD 4 + T淋巴细胞，释放TNFα并促进B细胞分泌AT 1-AA。当通过ET-1注入正常妊娠大鼠时，这些因素中的每一个都会引起高血压。由于人类数据暗示这些炎症因子在肥胖PE妊娠中被夸大，因此我的R 00的中心假设是肥胖和瘦素可以通过免疫机制夸大胎盘缺血诱导的高血压的发展，具体目的是测试以下假设：3）肥胖和慢性瘦素过量增强胎盘缺血诱导的CD 4 + T辅助细胞的增加，导致过度的高血压和肾ET-1。4）肥胖和慢性瘦素过量可增强胎盘缺血诱导的B细胞增加，导致高血压和AT 1-AA介导的肾ET-1反应。我有强有力的初步数据来支持我的假设，使用一个独特的肥胖妊娠大鼠模型（黑皮质素-4受体缺陷大鼠），我将计划将其与我已经学会的诱导大鼠胎盘缺血的技术和我计划学习的技术（如过继转移免疫细胞和流式细胞术）结合联合收割机，以验证我在本提案中的假设。因此，我的目标是通过研究胎盘缺血与高血压之间的联系来确定肥胖增加PE风险的途径。希望这些研究有助于制定治疗策略，以规避PE的发展。