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：
Lauren Alysse Biwer
金额：
$ 12.3万
依托单位：
TUFTS MEDICAL CENTER
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

来源：
https://reporter.nih.gov/project-details/10350128
关键词：
Adenoviruses Adipose tissue Adoptive Transfer Affect Angiotensin II Animal Model Animals Antigen Presentation Antigen Receptors Antigens Area Arteries Automobile Driving Biology Blood Pressure Blood Vessels C57BL/6 Mouse CD3 Antigens CD8B1 gene Cardiovascular Diseases Cardiovascular system Cells Clinical Data Dietary Sodium Disease Environment Evaluation Exhibits Exposure to Female Flow Cytometry Foundations Functional disorder Future Goals Heart Diseases Human Hypertension Hypoxia Immune Immunologic Techniques Immunology In Vitro Inflammation Inflammatory Injury KDR gene Kidney Knowledge Link Lymphoid Lymphoid Tissue Maternal Health Maternal Mortality Maternal Physiology Measures Mediating Medical center Mentors Mission Modeling Monoclonal Antibody HuM291 Mus Myocardial Infarction Nephrology Organ PTPRC gene Pathogenesis Phenotype Play Population Postpartum Hypertension Postpartum Period Pre-Eclampsia Pregnancy Pregnancy Complications Process Publishing RANTES Research Personnel Resistance Risk Role SELL gene Secondary Hypertension Sodium Chloride Stimulus Stress Stroke Structure Syndrome T cell therapy T memory cell T-Lymphocyte Techniques Testing Training Tumor-infiltrating immune cells United States National Institutes of Health Universities Vascular Diseases Vascular Proliferation Vascular remodeling Vasodilation Woman base cardiovascular risk factor cell motility chemokine cytokine epidemiologic data high risk human male hypertensive improved insight kidney cell male novel overexpression population migration prevent response systemic inflammatory response training opportunity vasoconstriction

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）是一种新高血压（HTN）的综合征，有器官损害发生 3-8％的怀孕，是孕产妇死亡率的主要原因。生存的女性未知机制的未来HTN，心脏病发作和中风的风险大大增加。这些妇女的血压和血管收缩对HTN压力的反应增强了 PE之后的几个月到几年。在雄性小鼠中，T细胞对于高血压和效应记忆T细胞有助于加剧对重复性高血压应激的反应。为了探索驱动PE后HTN的机制，我们修改了PE的两种模型。一个是由怀孕期间的抗血管生成可溶性VEGF受体1（SFLT1）的过表达和其他在怀孕期间由缺氧引起的。我确认这两个模型都会增加SFLT1 以及人类看到的PE的其他特征。 SFLT1模型中的初步数据表明，尽管产后SFLT1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刺激导致恶化血压反应，微血管血管收缩和T-的微血管表达细胞趋化因子，CCL5；（3）肾脏效应器记忆T细胞在 HTN刺激。因此，我建议检验以下假设，即实验性PE会导致长期T细胞 - 介导的微血管和肾脏的变化增加了对产后的敏感性 HTN刺激。 AIM 1将检查T细胞是否需要持续的血管重塑和 PE之后的功能障碍。将测量T细胞群体，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响应。然后，T细胞会耗尽，并血压和血管结构/功能分析。 AIM 2将确定是否收养暴露于PE的T细胞足以诱导与 PE PE HTN。 AIM 3将测试记忆T细胞在加剧对响应中的特定作用 PE之后的高血压刺激。目的的完成将为机制提供新的见解推动PE之后的HTN风险大幅增加，从而支持NIH任务改善孕产妇的健康。该提案还将允许我获得HTN疾病的新专业知识怀孕和基础免疫学技术。指导团队对此进行了集会应用，具有心血管免疫学，肾脏病，妊娠和血管方面的专业知识生物学，塔夫茨医学中心和塔夫茨大学的环境以及培训计划拟议的将进一步增强我成为研究人员学习的能力驱动女性心脏病的机制。