Mechanisms of post-preeclampsia hypertension

先兆子痫（PE）是一种新发高血压（HTN）的综合征，伴有器官损害， 怀孕的3-8%，是产妇死亡的主要原因。从体育课中幸存下来的女性 未来HTN、心脏病发作和中风的风险大幅增加，原因不明。 这些女性对HTN压力的血压和血管收缩反应增强， PE后持续数月至数年。在雄性小鼠中，T细胞是高血压所必需的， 效应记忆T细胞有助于对重复性高血压应激的加重反应。 为了探索PE后HTN的驱动机制，我们修改了两种PE模型;一种是由 抗血管生成可溶性VEGF受体1（sFlt 1）在妊娠期间的过度表达， 另一种是由妊娠期缺氧引起的。我证实，两种模型均导致sFlt 1增加 以及其他人类PE的特征。sFlt 1模型的初步数据显示，尽管 产后sFlt 1水平和血压正常化：（1）产后微血管 结构/功能异常持续存在;（2）产后HTN刺激导致 血压反应、微血管收缩和T- 细胞趋化因子，CCL 5;和（3）肾效应记忆T细胞在 HTN刺激。因此，我建议测试实验性PE导致长期T细胞- 微血管和肾脏介导的变化增加了对产后疾病的敏感性， HTN刺激。目的1将检查T细胞是否是持续血管重塑所必需的， PE后功能障碍将测量T细胞群、迁移和细胞因子表达 在PE期间和之后以及对高血压刺激的反应。然后T细胞将被耗尽， 血压和血管结构/功能分析。目标2将决定是否进行过继转移 暴露于PE的T细胞足以诱导与PE相关的血管和肾脏变化。 PE后HTN。目标3将测试记忆T细胞在加剧对免疫缺陷的反应中的特定作用。 PE后高血压刺激。目标的完成将为该机制提供新的见解 促使PE后HTN风险大幅增加，从而支持NIH的使命， 改善产妇保健。该提案还将使我获得HTN疾病的新专业知识 怀孕和基础免疫学技术。指导小组聚集在此 应用，具有心血管免疫学、肾脏病学、妊娠和血管 塔夫茨医学中心和塔夫茨大学的生物学、环境学和培训计划 建议将进一步加强我的能力，成为一个独立的调查研究 导致女性心脏病的机制

Preeclampsia (PE) is a syndrome of new hypertension (HTN) with organ damage that occurs in 3-8% of pregnancies and is a leading cause of maternal mortality. Women who survive PE have a substantially increased risk of future HTN, heart attack and stroke by unknown mechanisms. These women have enhanced blood pressure and vasoconstriction responses to HTN stress that persists months to years after PE. In male mice, T cells are necessary for hypertension and effector memory T cells contribute to exacerbated responses to repetitive hypertensive stresses. To explore mechanisms driving post-PE HTN, we modified two models of PE; one is induced by overexpression of the anti-angiogenic soluble VEGF receptor 1 (sFlt1) during pregnancy and the other is induced by hypoxia during pregnancy. I confirmed that both models cause increased sFlt1 and other features of PE seen in humans. Preliminary data in the sFlt1 model reveals that despite post-partum sFlt1 levels and blood pressure normalizing: (1) post-partum microvascular structure/function abnormalities persist; (2) post-partum HTN stimuli results in an exacerbated blood pressure response, microvascular vasoconstriction and microvascular expression of the T- cell chemokine, CCL5; and (3) kidney effector memory T cells are significantly increased after HTN stimuli. Thus, I propose to test the hypothesis that experimental PE causes long-term T cell- mediated changes in the microvasculature and kidney that increase sensitivity to post-partum HTN stimuli. Aim 1 will examine if T cells are necessary for persistent vascular remodeling and dysfunction after PE. T cell populations, migration and cytokine expression will be measured during and after PE and in response to hypertensive stimuli. T cells will then be depleted and blood pressure and vascular structure/function analyzed. Aim 2 will determine if adoptive transfer of T cells exposed to PE is sufficient to induce the vascular and kidney changes associated with post-PE HTN. Aim 3 will test the specific role of memory T cells in exacerbating the response to hypertensive stimuli after PE. Completion of the aims will provide new insight into the mechanism driving the substantial increase in HTN risk after PE, thereby supporting the NIH mission to improve maternal health. The proposal will also allow me to gain new expertise in HTN diseases of pregnancy and foundational immunology techniques. The mentoring team assembled on this application, with expertise in cardiovascular immunology, nephrology, pregnancy and vascular biology, the environment at Tufts Medical Center and Tufts University and the training plan proposed will further strengthen my ability to become an independent investigator studying mechanisms driving heart diseases in women.