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

• 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
• 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; 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

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.

长期的心理压力源，包括与工作有关的压力，社会经济地位差和社会隔离 - 所有最近的Covid-19锁定都提高了 - 是高血压和心血管的主要危险因素 疾病。压力激活的调节机制刺激交感神经系统升高血液 压力和重新分配到重要器官的血流已演变为生命保护措施。从一个 进化观点，通过长期敏感性增强心血管反应 机制对经过重复应激源的生物有利。但是，在现代社会中 应对压力的情况很少需要标记的血压升高，这些动作变为 有害的，由于心血管系统的反复不必要的超负荷施加不可逆的心脏，血管， 和肾脏伤害。彼此之间，对年轻人的压力源的增强心血管敏感性 个体与以后生活中高血压的风险密切相关。我们的长期目标是 研究确定压力引起的血压升高幅度的中心机制 为了确定新型的抗高血压治疗靶标。在这里，我们建议研究一种新的信号 由脑衍生的神经营养因子（BDNF）和雷帕霉素（MTOR）介导的级联反应 下丘脑（PVN）的室室核，这是一个在编排中起关键作用的大脑区域 神经内分泌和心血管应激反应。在压力期间，PVN中更新了BDNF的表达 响应增加的兴奋性输入和神经元活性。我们以前已经表明BDNF引起 PVN内的重要自适应变化以提高交感神经和血压。我们的初步 数据表明，BDNF刺激MTOR，作为PVN神经元中MTOR COVENCES-1（MTORC1）的一部分，MTORC1 可以从根本上改变神经元的形态和突触连通性，从而导致神经元升高 增加心血管应激反应并促进高血压的兴奋性。为了检验我们的假设，我们 采用一系列全面的体外斑块钳研究，神经元形态分析以及体内 使用病毒载体介导的BDNF和MTORC1的遗传操纵以及远程测光监测的实验 大鼠的心血管参数。在AIM 1中，我们测试MTORC1在PVN中的激活是否升高血液 压力，增加心血管应力反应，并介导BDNF的高血压作用。在AIM 2中，我们 确定BDNF-MTORC1信号是否调节PVN前的结构和功能特征 交感神经元，导致兴奋性增强。在AIM 3中，我们测试BDNF – MTORC1的抑制是否 防止慢性应激引起的高血压大鼠的高血压。这些研究具有潜力 通过确定BDNF – MTORC1轴作为非常重要的调节剂来显着推进该领域 自主和心血管功能决定了压力期间血压升高的放大器 并引起PVN中促进高血压发展的长期自适应机制。