# Early Life Stress Promotes an Inflammatory Phenotype Leading to Vascular Impairment and Lupus Nephritis Severity

> **NIH NIH F31** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2024 · $39,989

## Abstract

PROJECT SUMMARY
Exposure to early life stress (ELS) often is accompanied by adverse health outcomes earlier in adulthood and
with more severity such as in the case of Systemic Lupus Erythamateous (SLE), an autoimmune disease. The
risk for autoimmunity and cardiovascular disease (CVD) increases with ELS exposure and CVD is the
predominant cause for early mortality in SLE patients. This project addresses the gap in knowledge of why
coexistence with ELS is associated with higher prevalence and heart disease in SLE. In the case of SLE—
despite reports linking worsened disease activity in patients with ELS—there have been no studies in preclinical
rodent models of SLE in conjunction with ELS. Several investigations demonstrate that ELS is associated with
a pro-inflammatory phenotype and vascular dysfunction. In our mouse model of ELS, maternal separation with
early weaning (MSEW), we observed aortic endothelial dysfunction dependent on superoxide and increased
numbers of F4/80+ macrophages, an innate immune cell, in the adventitia of the aorta. In addition, vessel
dysfunction and aortic stiffness is exaggerated in MSEW mice subjected to pristane induction of SLE. We expect
impairment in vascular function is due to proinflammatory macrophage presence in MSEW animals. Preliminary
data shows mitochondrial dysfunction is present in MSEW mice indicating the superoxide impacting endothelial
dysfunction may be mitochondrial derived. Thus, our overall hypothesis states that ELS accentuates the
development and severity of aortic disease in a mouse model of SLE through mitochondrial-derived superoxide
production and activated pro-inflammatory macrophages. This project is designed with two specific aims. First,
we will determine if macrophages mediate development of aortic disease in ELS. We will use flow cytometry
and RNA sequencing to determine immune activation differences between MSEW and control mice. We then
will determine if absence of macrophages in vivo prevents MSEW vascular dysfunction compared to controls.
Second, studies will address if ELS mediates enhanced development of aortic disease in SLE through
mitochondrial superoxide production. The pristane-induced model of SLE will be used in conjunction with the
MSEW protocol to determine if oxidative stress, previously linked to SLE-mediated hypertension, is accelerated
by ELS. Experiments will examine markers for CVD in SLE using telemetry and vascular reactivity after ELS.
We will also measure CVD and disease after blocking mitochondrial superoxide by MitoTEMPOL. We expect to
see (i)elevated inflammatory macrophages that, when absent, reduce vascular dysfunction and (ii)a greater CVD
burden in MSEW SLE mice reduced by MitoTEMPOL treatment. This project is critical to begin to understand
the mechanistic relationship of ELS in SLE as well as crucial for studying immune driven diseases with CVD
complications. ELS is associated with adverse health outcomes in a variety of diseases. Advances in the ELS
fi...

## Key facts

- **NIH application ID:** 10897068
- **Project number:** 5F31HL165863-03
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Cailin Kellum
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $39,989
- **Award type:** 5
- **Project period:** 2022-08-22 → 2025-08-21

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10897068

## Citation

> US National Institutes of Health, RePORTER application 10897068, Early Life Stress Promotes an Inflammatory Phenotype Leading to Vascular Impairment and Lupus Nephritis Severity (5F31HL165863-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10897068. Licensed CC0.

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