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

项目1概要 早期生活压力（ELS）或18岁之前的创伤事件被确定为新的风险因素 对于心血管疾病（CVD）的研究已有20多年的历史，但对ELS的启动机制知之甚少。 博士Pollock和他的同事先前表明，暴露于ELS的年轻人的血管 与未暴露于ELS的患者相比，这些患者的功能障碍（脉搏波速度和外周阻力）明显增加。这些 数据表明，ELS在人类较早年龄时引发CVD风险。以前的报告发现，ELS影响 性别不同，因此在我们的研究中两性都被利用。项目1将研究分子和细胞 血管和免疫功能障碍的机制，以及一种策略，以扭转功能障碍， ELS的临床相关啮齿动物模型，母体分离（MaSep）。MaSep结合了心理社会学 在出生后-断奶前期间，反复将幼仔与母鼠分离的应激源。 了解ELS引发的整个发育过程中的分子机制对于制定战略至关重要， 降低CVD风险。ELS诱导的血管和免疫功能障碍介质的研究进展 该计划项目补助金（PPG）的强大理由。项目1发现，青春期前暴露于MaSep的小鼠 主动脉僵硬度（脉搏波速度）增加。此外，我们发现MaSep诱导内皮细胞 功能障碍，或一氧化氮（NO）损失和超氧化物（O2-）增加，线粒体DNA损伤更严重， 活化的巨噬细胞增加-所有描述的机制都有助于血管炎症和主动脉炎 刚度报告显示，微生物来源的短链脂肪酸（SCFAs）影响血管和免疫功能， 活动项目1特别发现，血浆丁酸，一种抗炎SCFA，在青春期前减少， 和暴露于MaSep的成年小鼠。项目2发现丁酸盐阻断了高血压的诱导 致敏项目1的中心假设是ELS启动血管和免疫功能障碍 通过内皮细胞和血管巨噬细胞系统的重新编程。两个目标将解决关键的 我们对ELS如何启动和维持血管和免疫功能障碍的理解存在差距， 接近。目标1将测试暴露于ELS是否通过以下途径引发血管和免疫功能障碍： 内皮细胞的重编程，特别关注组蛋白脱乙酰酶（HDAC）9和NADPH氧化酶 (NOX)二、实验利用诱导型内皮特异性HDAC 9或NOX 2敲除小鼠， 对于项目2，丁酸盐补充是否用多组学方法缓和血管功能障碍。目的 2将测试暴露于ELS是否通过重编程ELS启动血管和免疫功能障碍。 血管巨噬细胞活化。实验包括测定巨噬细胞耗竭或巨噬细胞- 特异性HDAC 9敲除逆转血管炎症，并且，在项目3和项目4中， 巨噬细胞活化与多组学方法。项目1研究具有翻译相关性， 确定丁酸盐补充是否会逆转ELS启动的内皮或巨噬细胞重编程。

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.