# Prospective Effects of Early Life Stress and Protective Factors on Vascular Function and Inflammation in Young Adulthood

> **NIH NIH P01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2023 · $365,132

## Abstract

PROJECT 4 SUMMARY
Early life stress (ELS), defined as adverse experiences occurring before age 18, is a highly prevalent risk
factor for cardiovascular disease (CVD). However, the development of effective strategies to prevent
CVD in individuals exposed to ELS is hindered by lack of knowledge about physiological pathways
underlying ELS effects on CVD, as well as malleable lifestyle factors that may mitigate these effects.
Cross-species animal studies guiding Project 1 and Project 2 implicate specific mechanistic pathways
that link ELS with CVD, including upregulation of histone deacetylase 9 (HDAC9), NADPH oxidase 2
(NOX2), and cytokines; reduced diversity in the gut microbiome; and reduction of short-chain fatty acids
(SCFA). Together, these pathways induce CVD through reprogramming of the immune and vascular
system in rodent models of ELS. However, we do not know whether these pathways lead to CVD in
people who experienced ELS and whether they can be modified by lifestyle factors, such as diet,
physical activity, and supportive parenting, during development. Project 4 will leverage an existing,
ethnically diverse cohort of 1,000 adults (age 29) from Birmingham, Alabama, who have been
characterized for ELS and lifestyle factors at ages 11, 13, 16, and 19, to test the hypotheses that 1) ELS
induces vascular dysfunction and hypertension through sustained pro-inflammatory reprogramming of
the gut microbiome and peripheral blood mononuclear cell transcriptome, and that 2) these effects may
be modified by protective lifestyle factors during development. The proposed assessment at age 29 will
include a comprehensive evaluation of stress and lifestyle factors in adulthood; vascular function; gut
microbiome; SCFAs; and peripheral blood mononuclear cell (PBMC) transcriptome. Data from all five
time points spanning ages 11 to 29 will be integrated to test 1) the relationship between prospectively
measured ELS and immune and vascular function in adulthood; 2) whether these relationships are
mediated by pro-inflammatory profiles of the gut microbiome and PBMC transcriptome in adulthood; and
3) whether diet quality, physical activity, and supportive parenting during development modify the
relationships between ELS and adult gut microbiome, PBMC transcriptome, and immune and vascular
function. Project 4 is conceptually and translationally innovative by testing specific gut microbiome and
transcriptome pathways discovered in rodents in humans. Together with Project 3 which tests
complementary metabolome and methylome pathways in adolescence, the two human projects will guide
future mechanistic studies by identifying new multi-omic pathways that link ELS with vascular dysfunction
during critical developmental periods spanning adolescence to young adulthood. The integrated findings
from this PPG will elucidate causal pathways and protective factors related to ELS-induced CVD risk,
directly informing the development of novel evidence-based interventions.

## Key facts

- **NIH application ID:** 10555128
- **Project number:** 1P01HL158500-01A1
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Sylvie Mrug
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $365,132
- **Award type:** 1
- **Project period:** 2023-02-15 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10555128

## Citation

> US National Institutes of Health, RePORTER application 10555128, Prospective Effects of Early Life Stress and Protective Factors on Vascular Function and Inflammation in Young Adulthood (1P01HL158500-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10555128. Licensed CC0.

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