Mechanisms of post-preeclampsia hypertension

子痫前期高血压的机制

基本信息

  • 批准号:
    10350128
  • 负责人:
  • 金额:
    $ 12.3万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-12-16 至 2023-11-30
  • 项目状态:
    已结题

项目摘要

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.
子痫前期(PE)是一种新的高血压综合征(HTN),发生在 3-8%的怀孕,是孕产妇死亡的主要原因。在体育比赛中幸存下来的女性 由未知机制导致的未来HTN、心脏病发作和中风的风险显著增加。 这些女性对HTN应激的血压和血管收缩反应增强 在PE后持续数月至数年。在雄性小鼠中,T细胞是高血压和 效应器记忆T细胞有助于加重对反复高血压应激的反应。 为了探索PE后HTN的驱动机制,我们对两种PE模型进行了改进;一种是由 抗血管生成的可溶性血管内皮生长因子受体1(SFlt1)在妊娠中的过度表达 另一种是孕期缺氧所致。我确认这两种模型都会导致sflt1增加 以及在人类身上看到的PE的其他特征。SFlt1模型的初步数据显示,尽管 产后sFlt1水平与血压正常化:(1)产后微血管 结构/功能异常持续存在;(2)产后HTN刺激导致 大鼠血压反应、微血管收缩及微血管表达 细胞趋化因子CCL5;(3)肾效应记忆T细胞显著增加 HTN刺激物。因此,我建议检验这样一种假设,即实验性PE导致长期T细胞- 增加产后敏感性的微血管和肾脏的中介变化 HTN刺激物。Aim 1将检查T细胞是否对持续性血管重塑和 PE后功能障碍。将测量T细胞群体、迁移和细胞因子的表达 在PE期间和之后,以及对高血压刺激的反应。然后T细胞就会耗尽, 分析血压和血管结构/功能。目标2将决定是否收养转移 暴露在PE中的T细胞的数量足以引起与之相关的血管和肾脏变化 后PE HTN。目标3将测试记忆T细胞在加剧对 PE后的高血压刺激物。这些目标的完成将为我们对这一机制提供新的见解 推动PE后HTN风险的大幅增加,从而支持NIH的使命 改善孕产妇健康。这项提议还将使我获得HTN疾病方面的新专业知识 怀孕和基础免疫学技术。指导团队就此集结 应用,在心血管免疫学、肾脏病、妊娠和血管方面具有专业知识 塔夫茨医学中心和塔夫茨大学的生物学、环境和培训计划 建议将进一步增强我成为一名独立调查员的能力 女性心脏病的致病机制。

项目成果

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Lauren Alysse Biwer其他文献

Lauren Alysse Biwer的其他文献

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{{ truncateString('Lauren Alysse Biwer', 18)}}的其他基金

Mechanisms of post-preeclampsia hypertension
子痫前期高血压的机制
  • 批准号:
    10541890
  • 财政年份:
    2021
  • 资助金额:
    $ 12.3万
  • 项目类别:

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