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

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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.