# Damage-Associated Molecular Patterns in Hypertension

> **NIH NIH P01** · AUGUSTA UNIVERSITY · 2020 · $1,888,532

## Abstract

PROGRAM SUMMARY PROGRAM DIRECTOR, WEBB
The integrating theme and unifying hypothesis of this program project centers on the role played by damage-
associated-molecular patterns (DAMPs) in hypertension. DAMPs are alarm signals generated from injured
host cells, damaged tissues or metabolic stress and are recognized by the innate immune system. We
hypothesize that sustained activation of the innate immune system in hypertension is maladaptive, leading to
activation of circulating neutrophils and monocytes in the peripheral circulation, which home to the vasculature,
and cause increased tissue destruction and low-grade inflammation. These inflammatory events contribute to
increased vasoconstriction, vascular remodeling, and renal injury that occur under the action of initiating
factors to increase blood pressure. Project 1 will test the hypothesis that in hypertension, exaggerated
apoptosis and necrosis in the vascular wall give rise to mitochondrial DNA (mtDNA), a DAMP that activates
Toll-like receptor 9 (TLR9) causing vascular inflammation, vasoconstriction and endothelial dysfunction. In
Project 2, it is hypothesized that cell death induces high mobility group box 1 (HMGB1) release and TLR4
activation resulting in dentritic cell (DC) and T cell activation and increases in blood pressure in both sexes.
However, due to a sex difference in the type of cell death, the molecular pathway driving immune-based
hypertension in females favors greater T regulatory cell (Treg) formation. This hypothesis predicts that
necrosis results in greater HMGB1 release and TLR4 activation in males leading to myeloid DC activation of
Th17 cells and increases in blood pressure and end-organ damage relative to females, while greater apoptosis
in females limits HMGB1 release and activates plasmacytoid DC to increase Treg formation limiting increases
in blood pressure and injury relative to males. Project 3 tests the hypothesis that high circulating DAMPs
stimulate inappropriate nitric oxide (NO) production by vasa recta (VR) endothelial cells in low sheer states.
This NO production is detrimental as it inhibits spontaneous rhythmic contractions of VR pericytes that
normally act to prevent red blood cell aggregations under these conditions. RBC occlusion of the VR then
leads to rarefaction of the surrounding medullary vasculature, impaired pressure-natriuresis and hypertension.
These conceptually unique approaches, combined with novel technological tools will advance our
understanding of the molecular and physiological mechanisms underlying the initiation of vascular injury and
end organ damage of hypertension. All projects will use the spontaneously hypertensive rat as an animal
model. This highly integrative and collaborative approach of the three component projects is supported by an
Administrative Core (Core A), the Animal Use and Instrumentation Core (Core B) and the Bioinflammation
Core (Core C).

## Key facts

- **NIH application ID:** 9859428
- **Project number:** 5P01HL134604-04
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Michael W. Brands
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,888,532
- **Award type:** 5
- **Project period:** 2017-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859428

## Citation

> US National Institutes of Health, RePORTER application 9859428, Damage-Associated Molecular Patterns in Hypertension (5P01HL134604-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9859428. Licensed CC0.

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