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总结 早期生活压力(ELS)，或18岁之前的创伤事件，被确定为一种新的危险因素 对于心血管疾病(CVD)，20多年前，人们对ELS的启动机制知之甚少。 波洛克博士和他的同事此前表明，接触ELS的年轻人有更高的血管 与没有接触ELS的人相比，功能障碍(脉搏波速度和外周阻力)。这些 数据表明，ELS在人类较早的年龄就会引发心血管疾病风险。之前的报告发现，ELS影响了 性别明显，因此在我们的研究中使用了两种性别。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一种逆转功能障碍的策略 临床相关的ELS啮齿动物模型，母体分离(MaSep)。MaSep结合了一种心理社会 出生后-断奶前反复将幼崽与母体分开的应激源。 了解ELS在发育过程中启动的分子机制对于制定策略是至关重要的 降低心血管疾病风险。ELS诱导的血管和免疫功能障碍的介质研究进展 这是该计划项目赠款(PPG)的强有力的理由。项目1发现，暴露于MaSep的青春期前小鼠 有增加的主动脉僵硬(脉搏波速度)。进一步，我们发现MaSep诱导内皮细胞 功能障碍，或一氧化氮(NO)和超氧阴离子(O2-)的丧失，线粒体DNA损伤更大，以及 激活的巨噬细胞增加--所有这些都描述了导致血管炎症和主动脉的机制 僵硬。研究表明，微生物衍生的短链脂肪酸(SCFA)影响血管和免疫。 活动。项目1特别发现，血浆丁酸盐，一种抗炎的单链脂肪酸，在青春期前减少 以及暴露于MaSep的成年小鼠。项目二发现丁酸盐阻断了高血压的诱导 敏化。项目1的中心假设是ELS引发血管和免疫功能障碍 通过内皮和血管巨噬细胞系统的重新编程。两个目标将解决关键问题 我们对ELS如何利用创新启动和维持血管和免疫功能障碍的理解存在差距 接近了。AIM 1将测试暴露于ELS是否通过以下途径启动血管和免疫功能障碍 内皮细胞的重新编程，特别是组蛋白脱乙酰酶(HDAC)9和NADPH氧化酶 (NOx)2.实验利用可诱导的内皮特异性HDAC9或NOX2基因敲除小鼠，并与 在项目2中，丁酸盐补充是否通过多组学方法缓解血管功能障碍。目标 2将测试暴露于ELS是否通过重新编程 血管巨噬细胞激活。实验包括巨噬细胞耗竭或巨噬细胞- 特定的HDAC9基因敲除可以逆转血管炎症，在项目3和项目4中， 用多组学方法激活巨噬细胞。项目1研究通过以下方式具有翻译相关性 确定丁酸盐补充是否会逆转ELS启动的内皮细胞或巨噬细胞重编程。