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.

先兆子痫 (PE) 是一种新发高血压 (HTN) 综合征，伴有器官损害，发生于 3-8% 的妊娠，是孕产妇死亡的主要原因。从PE中幸存下来的女性有由于未知的机制，未来患高血压、心脏病和中风的风险大大增加。这些女性对高血压应激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 细胞对于高血压和效应记忆 T 细胞会加剧对重复性高血压应激的反应。为了探索 PE 后 HTN 的驱动机制，我们修改了两种 PE 模型；一个是由引起妊娠期间抗血管生成可溶性 VEGF 受体 1 (sFlt1) 的过度表达以及另一种是怀孕期间缺氧引起的。我确认这两种模型都会导致 sFlt1 增加以及人类 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 刺激导致病情加剧血压反应、微血管血管收缩和 T- 的微血管表达细胞趋化因子，CCL5； (3) 肾脏效应记忆 T 细胞在治疗后显着增加高血压刺激。因此，我建议检验实验性 PE 导致长期 T 细胞- 介导微血管和肾脏的变化，增加对产后的敏感性高血压刺激。目标 1 将检查 T 细胞是否是持续血管重塑所必需的，以及 PE后功能障碍。将测量 T 细胞群、迁移和细胞因子表达 PE期间和之后以及对高血压刺激的反应。然后 T 细胞将被耗尽分析血压和血管结构/功能。目标 2 将确定是否采用收养转移暴露于 PE 的 T 细胞足以诱发与 PE 后 HTN。目标 3 将测试记忆 T 细胞在加剧反应中的具体作用 PE后的高血压刺激。目标的完成将为机制提供新的见解导致 PE 后 HTN 风险大幅增加，从而支持 NIH 的使命：改善孕产妇健康。该提案还将使我获得有关高血压疾病的新专业知识妊娠和基础免疫学技术。导师团队就此集结应用，具有心血管免疫学、肾病学、妊娠和血管学方面的专业知识塔夫茨医学中心和塔夫茨大学的生物学、环境以及培训计划提议将进一步增强我成为一名独立研究者的能力导致女性心脏病的机制。