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

 描述(申请人提供)：先兆子痫(PE)的发病率正在上升，这是妊娠期新发高血压的一种复杂疾病，需要研究肥胖等危险因素的日益流行如何夸大促进这种高血压的机制。尽管人类研究一直表明肥胖和体育之间存在正相关，但没有机械性的研究可言。经典研究表明，妊娠大鼠胎盘缺血导致胎盘释放抗血管生成因子，如由转录因子HIF-1α介导的可溶性FMS样1酪氨酸激酶(sFlt-1)，进入母体循环，在那里它拮抗胎盘生长因子和血管内皮生长因子，导致肾脏内皮素-1(ET-1)升高，进而引发高血压。人类数据显示，sflt-1和肥胖相关代谢因子瘦素可能与肥胖的体育女性高血压程度更高有关。因此，My K99的中心假设是肥胖和瘦素通过HIF-1α依赖的机制放大胎盘缺血诱导的sFlt-1的产生，该机制通过ET-1介导过度的血压反应，并有针对性地检验假设：1)肥胖和瘦素通过HIF-1α依赖的机制促进缺氧和/或胎盘缺血诱导的胎盘sFlt-1的产生；2)肥胖和瘦素通过ET-1信号加剧胎盘缺血或慢性sFlt-1过度的血压和肾脏血流动力学。我的R00期的基本原理是胎盘缺血通过激活母体CD_4+T淋巴细胞而引发促炎反应，从而释放肿瘤坏死因子α并促进B细胞分泌AT_1-AA。当通过ET-1将这些因素注入正常妊娠大鼠体内时，每种因素都会导致高血压。由于人类数据提示这些炎症因子在肥胖的PE妊娠中被夸大，My R00的中心假设是肥胖和瘦素可通过免疫机制夸大胎盘缺血诱导的高血压的发展，并针对以下假设进行特定目的的检验：3)肥胖和慢性瘦素过量增强胎盘缺血诱导的CD+T辅助细胞增加，从而导致肿瘤坏死因子α介导的高血压和肾脏ET-1反应过度，以及4)肥胖和慢性瘦素过量增强胎盘缺血诱导的B细胞增加，导致由AT1-AA介导的高血压和肾脏ET-1反应过度。我有强大的初步数据支持我的假设，使用的是一种独特的肥胖怀孕大鼠模型(黑素皮质素-4受体缺陷大鼠)，我将计划将该模型与我已学到的诱导大鼠胎盘缺血的技术以及我计划学习的技术相结合，如免疫细胞过继转移和流式细胞术，以检验我在该提案中的假设。因此，我的目标是通过研究胎盘缺血与高血压之间的联系，找出肥胖增加PE风险的途径。希望这些研究有助于制定治疗策略，以绕过发展中的PE。

 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.