Early Life Stress Induced Reprogramming of Vascular Function by the Endothelium and Macrophage Systems

生命早期的压力诱导内皮细胞和巨噬细胞系统对血管功能进行重新编程

• 批准号: 10555125
• 负责人: Jennifer S Pollock
• 金额: $ 38.85万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555125
• 关键词: 21 year old; Adolescence; Adolescent; Adult; Affect; Age; Anti-Inflammatory Agents; Aorta; Blood Pressure; Blood Vessels; Brain; Butyrates; Cardiovascular Diseases; Child; Childhood; Collaborations; Colony-Stimulating Factor Receptors; DNA Damage; Data; Development; Economic Burden; Endothelial Cells; Endothelium; Epigenetic Process; Exposure to; Functional disorder; Future; Gene Expression; HDAC9 gene; Healthcare; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; Hypertension; Immune; Immune System Diseases; Inflammatory; Kidney; Knock-out; Knockout Mice; Link; Macrophage; Macrophage Activation; Macrophage Colony-Stimulating Factor; Measures; Mediating; Mediator; Mitochondrial DNA; Molecular; Molecular Profiling; Mus; NADPH Oxidase; Nitric Oxide; Pathway interactions; Peripheral Resistance; Physiologic pulse; Physiological; Plasma; Production; Program Research Project Grants; Receptor Inhibition; Reporting; Rodent Model; Signal Pathway; Signal Transduction; Societies; Spleen; Superoxides; Supplementation; System; Testing; Tissues; Transgenic Mice; Translating; Tunica Adventitia; Vascular Diseases; Volatile Fatty Acids; Weaning; Work; arterial stiffness; cardiovascular disorder risk; cardiovascular risk factor; care burden; childhood adversity; clinically relevant; early life stress; endothelial dysfunction; epigenome; experience; experimental study; indexing; innovation; maternal separation; microbial; monocyte; mouse model; multiple omics; novel; postnatal; prepuberty; programs; psychosocial stressors; pup; resilience; sex; synergism; timeline; transcriptome; traumatic event; vascular inflammation; young adult

PROJECT 1 SUMMARY Early life stress (ELS), or traumatic events during the years prior to age 18, was identified as a novel risk factor for cardiovascular disease (CVD) over 20 years ago yet little is understood about the ELS-initiating mechanisms. Dr. Pollock and colleagues previously showed that young adults with ELS exposure have higher vascular dysfunction (pulse wave velocity and peripheral resistance) compared to those with no ELS exposure. These data indicate that ELS initiates CVD risk at earlier ages in humans. Previous reports find that ELS impacts the sexes distinctly, thus both sexes are utilized in our studies. Project 1 will investigate the molecular and cellular mechanisms of vascular and immune dysfunction as well as a strategy to reverse the dysfunction using a clinically relevant rodent model of ELS, maternal separation (MaSep). MaSep incorporates a psychosocial stressor of repeated periods of separation of pups from dams during the postnatal-preweaning period. Understanding the ELS-initiated molecular mechanisms across development is essential to devise strategies to mitigate CVD risk. Progress in studying the mediators of ELS-induced vascular and immune dysfunction provides a strong rationale for this Program Project Grant (PPG). Project 1 finds that pre-pubertal mice exposed to MaSep have increased aortic stiffness (pulse wave velocity). Further, we found that MaSep induces endothelial dysfunction, or loss of nitric oxide (NO) and increased superoxide (O2-), greater mitochondrial DNA damage, and increased activated macrophages—all described mechanisms contributing to vascular inflammation and aortic stiffness. Reports show that microbial-derived short chain fatty acids (SCFAs) affect vascular and immune activity. Project 1 found specifically that plasma butyrate, an anti-inflammatory SCFA, is reduced in pre-pubertal and adult mice exposed to MaSep. Project 2 found that butyrate blocked the induction of hypertension sensitization. The central hypothesis of Project 1 is that ELS initiates vascular and immune dysfunction through reprogramming of the endothelium and vascular macrophage systems. Two aims will address the critical gaps in our understanding of how ELS initiates and sustains vascular and immune dysfunction utilizing innovative approaches. Aim 1 will test whether exposure to ELS initiates vascular and immune dysfunction through reprogramming of the endothelium, specifically focused on histone deacetylase (HDAC) 9 and NADPH oxidase (NOX) 2. Experiments utilize inducible endothelium-specific HDAC9 or NOX2 knockout mice and, in collaboration with Project 2, whether butyrate repletion moderates the vascular dysfunction with a multi-omic approach. Aim 2 will test whether exposure to ELS initiates vascular and immune dysfunction through reprogramming of vascular macrophage activation. Experiments include determinations of macrophage depletion or macrophage- specific HDAC9 knockout reverses vascular inflammation, and, with Project 3 and Project 4, a timeline of macrophage activation with a multi-omic approach. Project 1 studies have translational relevance by determinations whether butyrate repletion will reverse ELS-initiated endothelium or macrophage reprogramming.

项目1摘要 在18岁之前的几年中，早期的生活压力（EL）或创伤事件被确定为新型风险因素 对于20年前的心血管疾病（CVD），关于ELS发射机制几乎没有理解。 Pollock博士及其同事先前表明，ELS暴露的年轻人的血管较高 与没有ELS暴露的功能障碍（脉搏波速度和外围电阻）相比。这些 数据表明ELS在人类的早期启动CVD风险。先前的报告发现ELS会影响 性别明显，因此在我们的研究中使用了两个性别。项目1将研究分子和细胞 血管和免疫功能障碍的机制以及使用A逆转功能障碍的策略 EL的临床相关啮齿动物模型，物质分离（MASEP）。 MASEP结合了一个社会心理 在产后聚会期间，幼崽与大坝分离的重复时期的压力源。 了解跨开发的ELS发起的分子机制对于制定策略至关重要 减轻CVD风险。研究ELS诱导的血管和免疫功能障碍的介体的进展提供了 该计划项目赠款（PPG）的有力理由。项目1发现，前小鼠暴露于MASEP 主动脉刚度增加（脉冲波速度）。此外，我们发现MASEP诱导内皮 功能障碍或一氧化氮（NO）和超氧化物（O2-）的丧失，线粒体DNA损伤较大，并且 激活的巨噬细胞增加 - 所有描述了导致血管感染和主动脉的机制 刚性。报告显示，微生物衍生的短链脂肪酸（SCFA）会影响血管和免疫 活动。项目1专门发现，抗炎SCFA的血浆丁酸酯在预伯伯氏症中减少了 和成年小鼠暴露于MASEP。项目2发现，丁酸酯阻止了高血压的诱导 致敏。项目1的中心假设是ELS启动血管和免疫功能障碍 通过重新编程内皮和血管巨噬细胞系统。两个目标将解决关键 我们对ELS如何发起和自杀的差距，利用创新的血管和免疫功能障碍 方法。 AIM 1将测试暴露于ELS是否会引起血管和免疫功能障碍 重新编程内皮，专门针对组蛋白脱乙酰基酶（HDAC）和NADPH氧化酶 （NOX）2。实验利用可诱导的内皮特异性HDAC9或NOX2敲除小鼠，并在协作中 通过项目2，是否丁酸替代可以通过多摩变方法调节血管功能障碍。目的 2将测试暴露于ELS是否通过重新编程来启动血管和免疫功能障碍 血管巨噬细胞激活。实验包括确定巨噬细胞耗竭或巨噬细胞 - 特定的HDAC9敲除逆转血管注射，并且在项目3和项目4的情况下， 巨噬细胞通过多摩变方法激活。项目1研究具有翻译相关性 确定丁酸酯替代是否会逆转ELS发射的内皮或巨噬细胞重编程。