Hypothalamic BDNF-mTOR signaling promotes hypertension by increasing cardiovascular sensitivity to stress

下丘脑 BDNF-mTOR 信号通过增加心血管对压力的敏感性促进高血压

基本信息

批准号：
10736248
负责人：
Benedek Erdos
金额：
$ 60.27万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-21 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736248
关键词：
Animals Antihypertensive Agents Blood Pressure Blood Vessels Blood flow Brain Brain region Brain-Derived Neurotrophic Factor COVID-19 Cardiac Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Characteristics Chronic Chronic stress Complex Conscious Data Development Electrophysiology (science)Equilibrium FRAP1 gene Female Future Glutamates Goals Hypertension Hypothalamic structure Immunofluorescence Immunologic In Vitro Individual Life Measures Mediating Metabolic Modeling Modernization Monitor Morphology Neuronal Plasticity Neurons Neurosecretory Systems Organ Organism Output Pathway interactions Physiological Play Predisposition Psychological Stress Public Health Rattus Regulation Research Risk Risk Factors Role Signal Transduction Slice Social isolation Societies Socioeconomic Status Spinal Stimulus Stress Sympathetic Nervous System Synapses Synaptic Transmission Techniques Telemetry Testing Vertebral column Viral Vector Work acute stress biological adaptation to stress blood pressure elevation blood pressure reduction cardiovascular health cardiovascular risk factor clinically relevant coping density experimental study genetic manipulation hypertensive in vivo male multidisciplinary neural circuit neuronal cell body neuronal circuitry neuronal excitability neurotransmission new therapeutic target normotensive novel paraventricular nucleus patch clamp prevent psychologic psychological stressor renal damage response sensor stressor therapeutic target transmission process

项目摘要

Chronic psychological stressors, including work-related stress, poor socioeconomic status and social isolation — all heightened by recent Covid-19 lockdowns — are major risk factors for hypertension and cardiovascular disease. Stress-activated regulatory mechanisms that stimulate the sympathetic nervous system to elevate blood pressure and redistribute blood flow to vital organs have evolved as life-protecting measures. From an evolutionary perspective, enhancing cardiovascular responses through long-term sensitization of these mechanisms is advantageous to organisms subjected to repeated stressors. However, in modern society, where coping with stressful situations rarely requires marked elevations in blood pressure, these actions become detrimental, as repeated unnecessary overload of the cardiovascular system exerts irreversible cardiac, vascular, and renal damage. Accordingly, augmented cardiovascular sensitivity to stressors in young, normotensive individuals is strongly correlated with the risk of becoming hypertensive later in life. Our long-term goal is to investigate the central mechanisms that determine the magnitude of blood pressure elevations elicited by stress in order to identify novel anti-hypertensive therapeutic targets. Here, we propose to investigate a novel signaling cascade mediated by brain-derived neurotrophic factor (BDNF) and mechanistic target of rapamycin (mTOR) in the paraventricular nucleus of the hypothalamus (PVN), a brain region that plays a key role in orchestrating neuroendocrine and cardiovascular stress responses. BDNF expression is upregulated in the PVN during stress in response to increased excitatory input and neuronal activity. We have previously shown that BDNF elicits important adaptive changes within the PVN to elevate sympathetic activity and blood pressure. Our preliminary data suggest that BDNF stimulates mTOR, as part of mTOR complex-1 (mTORC1) in PVN neurons, and mTORC1 can fundamentally change neuronal morphology and synaptic connectivity, resulting in elevated neuronal excitability to augment cardiovascular stress responses and promote hypertension. To test our hypothesis, we employ a comprehensive array of in vitro patch-clamp studies, neuronal morphology analysis, as well as in vivo experiments using viral vector-mediated genetic manipulation of BDNF and mTORC1 and telemetric monitoring of cardiovascular parameters in rats. In Aim 1, we test whether mTORC1 activation in the PVN elevates blood pressure, augments cardiovascular stress responses, and mediates hypertensive actions of BDNF. In Aim 2, we determine whether BDNF–mTORC1 signaling regulates structural and functional characteristics of PVN pre- sympathetic neurons, resulting in enhanced excitability. In Aim 3, we test whether inhibition of BDNF–mTORC1 prevents chronic stress-induced hypertension in borderline hypertensive rats. These studies have the potential to significantly advance the field by establishing the BDNF–mTORC1 axis as a highly important regulator of autonomic and cardiovascular function that determines the amplitude of blood pressure elevations during stress and elicits long-term adaptive mechanisms in the PVN that promote the development of hypertension.

慢性心理压力源，包括与工作相关的压力、不良的社会经济地位和社会孤立—— 最近 Covid-19 封锁导致的所有哮喘都是高血压和心血管疾病的主要危险因素压力激活的调节机制刺激交感神经系统升高血液。压力和重新分配重要器官的血流已发展成为生命保护措施。从进化的角度来看，通过对这些物质的长期敏化来增强心血管反应机制有利于遭受反复应激的生物体。然而，在现代社会中。应对压力情况很少需要显着升高血压，这些行为变得疼痛，因为心血管系统反复不必要地超负荷，对心脏、血管、因此，血压正常的年轻人的心血管对压力源的敏感性增强。个体与晚年患高血压的风险密切相关。我们的长期目标是研究决定压力引起的血压升高程度的中心机制为了确定新的抗高血压治疗靶点，我们建议研究一种新的信号传导。脑源性神经营养因子（BDNF）和雷帕霉素（mTOR）机制靶点介导的级联反应下丘脑室旁核（PVN），一个在协调中发挥关键作用的大脑区域神经内分泌和心血管应激反应期间 PVN 中 BDNF 表达上调。我们之前已经证明 BDNF 会引起兴奋性输入和神经活动的增加。我们的初步研究表明，PVN 内的重要适应性变化可提高交感神经活动和血压。数据表明 BDNF 刺激 mTOR，作为 PVN 神经元中 mTOR 复合物 1 (mTORC1) 的一部分，并且 mTORC1 可以从根本上改变神经元形态和突触连接，导致神经元兴奋性会增强心血管应激反应并促进高血压。为了检验我们的假设，我们。采用一系列全面的体外膜片钳研究、神经形态分析以及体内使用病毒载体介导的 BDNF 和 mTORC1 基因操作以及遥测监测进行实验在目标 1 中，我们测试了 PVN 中的 mTORC1 激活是否会升高血液水平。压力，增强心血管应激反应，并介导 BDNF 的高血压作用。确定 BDNF-mTORC1 信号传导是否调节 PVN 前体的结构和功能特征交感神经元，导致兴奋性增强。在目标 3 中，我们测试是否抑制 BDNF-mTORC1。预防边缘性高血压大鼠的慢性应激性高血压。这些研究具有潜力。通过将 BDNF-mTORC1 轴建立为非常重要的调节因子，显着推进该领域的发展自主神经和心血管功能决定压力期间血压升高的幅度并在 PVN 中引发长期适应机制，促进高血压的发展。