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

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，包括与工作有关的压力、较差的社会经济地位和社会孤立- 所有这些都因最近新冠肺炎被封锁而加剧-是高血压和心血管疾病的主要危险因素 疾病。刺激交感神经系统升高血液的应激激活调节机制 压力和将血液重新分配到重要器官已演变为保护生命的措施。从一个 从进化的角度，通过对这些物质的长期敏化来增强心血管反应 机制对遭受反复应激源的生物体有利。然而，在现代社会中， 应对有压力的情况很少需要血压显著升高，这些行动成为 有害的，因为反复的不必要的心血管系统过载会造成不可逆的心脏，血管， 和肾脏损伤。因此，血压正常的年轻人心血管对应激源的敏感性增强 个体与晚年患高血压的风险密切相关。我们的长期目标是 研究决定应激引起的血压升高幅度的中枢机制 以寻找新的降压治疗靶点。在这里，我们建议研究一种新的信令 脑源性神经营养因子(BDNF)和雷帕霉素的机制靶点(MTOR)介导的级联反应 下丘脑室旁核(PVN)是大脑的一个区域，在协调 神经内分泌和心血管应激反应。应激过程中室旁核BDNF表达上调 以应对兴奋性输入和神经元活动的增加。我们之前已经证明，BDNF可以诱导 室旁核内重要的适应性变化，以提高交感神经活性和血压。我们的预赛 数据表明，BDNF刺激PVN神经元中的mTOR，作为mTOR复合体1(MTORC1)的一部分，以及mTORC1 可以从根本上改变神经元的形态和突触连接，导致神经元升高 兴奋性，以增强心血管应激反应和促进高血压。为了检验我们的假设，我们 采用了一系列全面的体外膜片钳研究、神经元形态分析以及体内研究 病毒载体介导的BDNF和mTORC1基因操作及遥测监测实验 大鼠心血管参数的变化。在目标1中，我们测试了PVN中mTORC1的激活是否会升高血液 压力，增强心血管应激反应，并介导BDNF的升压作用。在目标2中，我们 确定BDNF-mTORC1信号是否调节PVN Pre-2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，我们测试了BDNF-mTORC1的抑制作用 预防临界高血压大鼠的慢性应激性高血压。这些研究有可能 通过建立BDNF-mTORC1轴作为一种非常重要的调节因子来显著推进该领域 自主神经和心血管功能决定应激时血压升高的幅度 并得出PVN中促进高血压发生发展的长期适应机制。