Effect of obesity on antiangiogenic and inflammatory mechanisms of hypertension

肥胖对高血压抗血管生成和炎症机制的影响

• 批准号: 9756451
• 负责人: Frank Travis Spradley
• 金额: $ 24.9万
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756451
• 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; Chronic; Complex; Data; Development; Disease; Endothelin-1; Endothelin-2; Endothelium; Excretory function; Fetal Death; Flow Cytometry; Goals; Grant; Human; Hypertension; Hypoxia; Immune; Immune response; Incidence; Inflammatory; Inflammatory Response; Infusion procedures; Ischemia; Kidney; Laboratories; Learning; Leptin; Link; Maternal Mortality; Mediating; Melanocortin 4 Receptor; Mentors; Metabolic; Modeling; Obesity; Overweight; Pathway interactions; Perfusion; Phase; Placenta; Placental Growth Factor; Placentation; Plasma; Plasma Cells; Population; Pre-Eclampsia; Predictive Factor; Pregnancy; Pregnant Women; Premature Birth; Prevalence; Production; Protein Tyrosine Kinase; Rattus; Reporting; Risk; Risk Factors; Signal Transduction; Stimulus; T-Lymphocyte; TNF gene; Techniques; Testing; Uterus; Vascular Endothelial Growth Factors; Weight; Woman; effective therapy; experimental study; hemodynamics; human data; insight; maternal hypertension; maternal morbidity; novel; perinatal morbidity; pregnant; pressure; receptor; reproductive; 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）是一种妊娠期新发高血压的复杂疾病，其发病率正在上升，需要进行研究来检验肥胖等危险因素的日益流行如何夸大了促进这种高血压的机制。尽管人类研究一致表明肥胖与早泄之间存在正相关关系，但尚无机制研究可言。对此类机制的深入了解来自于经典研究，该研究表明妊娠大鼠胎盘缺血会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，拮抗胎盘生长因子 (PlGF) 和血管内皮生长因子 (VEGF)，从而引起肾血管生成增加。 内皮素-1 (ET-1) 然后是高血压。人类数据强调了 sFlt-1 和肥胖相关代谢因子瘦素与肥胖 PE 女性高血压之间可能存在的联系。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 产生，该机制通过 ET-1 介导过度的血压反应，具体目的是测试以下假设：1) 肥胖和瘦素增强缺氧和/或胎盘缺血诱导的胎盘缺血性增加中 sFlt-1 的产生。 HIF-1α 依赖性机制，2) 肥胖和瘦素通过 ET-1 信号传导加剧血压和肾血流动力学，导致胎盘缺血或慢性 sFlt-1 过量。我的 R00 阶段的基本原理是，胎盘缺血会引发促炎反应，激活母体 CD4+ T 淋巴细胞，释放 TNFα 并促进 B 细胞分泌 AT1-AA。当通过 ET-1 输注到正常怀孕大鼠体内时，这些因素中的每一个都会导致高血压。由于人类数据暗示这些炎症因子在肥胖 PE 妊娠中被夸大，我的 R00 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发的高血压的发展，具体目的是测试以下假设：3) 肥胖和慢性瘦素过量会增强胎盘缺血诱发的 CD4+ T 辅助细胞增加，从而导致 TNFα 介导的过度高血压和肾脏 ET-1 反应，4) 肥胖和慢性瘦素过量会增强胎盘缺血诱导的 B 细胞增加，导致 AT1-AA 介导的过度高血压和肾脏 ET-1 反应。我有强有力的初步数据来支持我的假设，使用一种独特的肥胖怀孕大鼠模型（黑皮质素-4受体缺陷型大鼠），我计划将其与我已经学会的诱导大鼠胎盘缺血的技术以及我计划学习的技术（例如免疫细胞的过继转移和流式细胞术）结合起来，以测试我在本提案中的假设。因此，我的目标是通过检查胎盘缺血与高血压之间的联系机制来确定肥胖增加 PE 风险的途径。希望这些研究有助于制定治疗策略，以避免 PE 的发展。