# A Role of GAS6/Axl Signaling in the Development of Essential Hypertension

> **NIH VA IK2** · RALPH H JOHNSON VA MEDICAL CENTER · 2021 · —

## Abstract

PROJECT SUMMARY
Hypertension is the leading cause of morbidity and mortality from stroke, myocardial infarction, heart
failure, and chronic kidney disease amongst the United States Veterans. Despite the importance of
blood pressure control, the pathogenesis of essential hypertension remains poorly understood.
Recently, a new observation has shed light onto potential dendritic cells (DCs) that may be involved in
human hypertension. Using single-cell ribonucleic acid (RNA) sequencing, a new subset of DCs has
been described with surface expression of Axl and Siglec-6 in normal health subjects. They showed
that Axl+ Siglec-6+ DCs (AS DCs) can potently drive T cell proliferation and produce large amounts of
pro-inflammatory cytokines. Based on previously published studies and preliminary data, I propose that
hypertension leads to the release of endothelial-derived growth arrest specific 6 (GAS6) that activates
Axl on DCs leading to inflammation and its associated end organ damage. In Aim 1, I will test the
hypothesis that hypertensive stimuli lead to GAS6/Axl-dependent inflammasome activation mediated
by reactive oxygen species (ROS) in AS DCs. In this aim, I will expose human CD14+ monocytes to
GAS6 or hypertensive endothelial cell stretch and assess inflammasome activation, ROS production,
and the formation of the highly reactive Isolevuglandin (isoLG)-adducts by flow cytometry. I will also
examine the role of isoLGs on inflammasome activation by scavenging isoLGs using 2-
hydroxybenzilamine (2-HOBA) during exposure of human monocytes to hypertensive stimuli and
assess cytokine production by flow cytometry. Lastly, I will examine the response of AS DCs from
normotensive and hypertensive human subjects in an unbiased fashion by cellular indexing of
transcriptomes and epitopes by sequencing (CITE-seq). I predict that scavenging ROS and/or isoLGs
during exposure of GAS6 or endothelial cell stretch will prevent inflammasome activation and pro-
inflammatory cytokine release by AS DCs. In Aim 2, I will test the hypothesis that Axl-dependent
signaling in DCs promotes hypertension and its associated end-organ damage. I will use mice in which
I have deleted Axl specifically in DCs (Axlfl/fl and AxlCD11cCre). I will examine the in vivo role of Axl in DCs
during hypertension by radiotelemetry and flow cytometry. Next, I will investigate the deletion of Axl in
DCs on inflammasome activation and T cell proliferation in vitro by flow cytometry. I predict that genetic
deletion of Axl will prevent hypertension, DC activation, and its associated inflammation. In Aim 3, I will
test the hypothesis that GAS6 promotes DC activation, hypertension, and its associated inflammation
I will use mice that have genetic deletion for GAS6 (GAS6WT/WT and GAS6-/-). I will examine the in vivo
role of GAS6 by performing bone marrow transplantation studies and assess DC activation and
development of hypertension by flow cytometry and radiotelemetry. I will genetically delete GAS6 from...

## Key facts

- **NIH application ID:** 10610110
- **Project number:** 7IK2BX005605-02
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** Justin Pieter Van Beusecum
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 7
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10610110

## Citation

> US National Institutes of Health, RePORTER application 10610110, A Role of GAS6/Axl Signaling in the Development of Essential Hypertension (7IK2BX005605-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10610110. Licensed CC0.

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