Early Life Stress-induced Reprogramming of Ambulatory Blood Pressure and Vascular Function in Adolescence

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PROJECT 3 SUMMARY Early life stress (ELS) was strongly linked with adult-onset cardiovascular disease (CVD) over 20 years ago but remains an under-appreciated CVD risk factor. More than half of U.S. adults report ELS exposures such as household dysfunction, abuse, or neglect in childhood. Our publications have shown that adults with ELS have increased indicators for future CVD risk, including casual blood pressure (BP), pulse wave velocity (PWV), and circulating pro-inflammatory factors. Projects 1 and 2 show that animal models of ELS have hypertension sensitization, increased sympathetic drive, vascular dysfunction, and activation of pro-inflammatory macrophages that are known drivers of CVD risk. There are gaps in our knowledge of how ELS affects indicators for future CVD risk in adolescence, and whether the same pathways in animal models of ELS are associated with CVD risk in people. Therefore, the principal focus of Project 3 is to address these gaps during adolescence to identify critical clinical features and molecular pathways in ELS-associated CVD risk, with the potential to guide early interventions to prevent or mitigate CVD. Our preliminary data further support the rationale for Project 3, showing that adolescents with ELS have increased vascular stiffness and ambulatory diastolic BP along with pro-inflammatory metabolite patterns in plasma and gene methylation patterns in circulating monocytes. The central hypothesis of Project 3 is that ELS promotes vascular stiffness and abnormal ambulatory BP in adolescents through pro-inflammatory reprogramming of the circulating metabolome and monocyte epigenome. Our cross-sectional study design utilizes comprehensive cardiovascular and multi- omics profiling in racially diverse adolescent girls and boys in Alabama. Aim 1 will test the hypothesis that adolescents exposed to ELS will have increased vascular stiffness and ambulatory blood pressure. Collaborative experiments will also compare differences in CVD risk indicators in adolescents (Project 3) vs. adults (Project 4) and study heart rate and BP variability as surrogates for increased sympathetic drive along with Project 2. Aim 2 will test the hypothesis that ELS is associated with pro-inflammatory patterns in the plasma metabolome and monocyte epigenome in adolescents. Collaborative experiments will specifically focus on short chain fatty acids (SCFA) and methylation of HDAC9 and NOX2 genes as in animal models of ELS from Projects 1 and 2. We will integrate our metabolome and methylome data in adolescents with complementary microbiome, metabolome, and transcriptome data in adults from Project 4 to discover new multi-omic pathways that link ELS with vascular dysfunction from adolescence to adulthood. Project 3 is conceptually innovative by testing our central hypothesis in adolescents to help identify targets for future intervention studies to prevent ELS-associated CVD. The proposed work has translational relevance by applying basic science discoveries from Projects 1 and 2 (SCFA-associated vascular dysfunction, pro-inflammatory gene methylation patterns, and increased sympathetic drive) to develop the central hypothesis and aims.