# Targeting Biomechanical Signaling in AAA

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2024 · —

## Abstract

Abdominal aortic aneurysms (AAA) afflict ~8% of Americans and ruptured AAA carries >80% mortality.
Screening programs have increased identification of small AAA, but there is no directed medical therapy to inhibit
growth and rupture rates have not decreased. The technologic advances in endovascular AAA repair have been
vast while our ability to correlate pathology to clinical care has lagged. There is a clear need for a platform to
incorporate patient-specific mechanobiologic stressors to complement aortic diameter measurements and inform
treatment decisions. Inhibition of two mechanical signaling molecules, the AngiotensinII-type 1 receptor (AT1R)
and the serum and glucocorticoid inducible kinase-1 (SGK-1), has been explored in pre-clinical experimentation
and hold promise for clinical application. In mice treated with the AT1R blocker Losartan or SGK-1 inhibitor
EMD638683, AAA growth was abrogated and only ~25% aortic dilation was observed, suggesting that there was
a non-mechanical contribution to this early matrix remodeling. Additionally, since both inhibitors led to the same
degree of aortic remodeling, it has raised the question of whether AT1R and SGK-1 operate interdependent
mechanical signaling cascades. Interest in SGK-1 as a druggable target in small AAA was amplified when it was
discovered that upregulated SGK-1 activity promoted VSMC pro-inflammatory cytokine synthesis, while SGK-1
inhibition restored VSMC contractile function as quantified by ultrasound-derived pulse propagation velocity
(PPV). Therefore, SGK-1 is a prime candidate to transduce aortic mechanical strain to promote VSMC synthetic
activity in AAA growth. We propose that VSMC synthetic phenotypes evolve during AAA growth based on
mechanical activation of SGK-1 and that the plasma levels of well-documented AAA biomarkers represent an
opportunity to define these transitions. Specific biomarkers assessed in this project incorporate inflammatory
cytokines (Interleukin-6, IL-6), protease systems (Matrix metalloproteinse-9, MMP-9; CathepsinS, CtsS;
CystatinC, CysC), markers of calcification (Osteoprotegerin, OPG), and fibrillar matrix peptides (TenascinC,
TNC). Integrating these pathologic matrix markers (PMMs) with ultrasound-derived mechanical aortic strain and
immunohistochemical analysis may enable prediction of aortic wall instability. We hypothesize that increased
aortic stiffness can mechanically activate SGK-1 to alter VSMC synthetic activity to promote PMM production,
aortic matrilysis, and AAA growth. In Aim 1, stimulation with axial tension will confirm upregulated SGK-1 activity
in murine abdominal aortic rings. Dependence of PMM expression on SGK-1 activity will be explored by blocking
with EMD638683 versus Losartan. Data will be computationally integrated to explore additional pathways
engaged in tension-induced VSMC synthetic activity. In Aim 2, mice will undergo AAA induction with peri-
adventitial application of CaCl2. Ultrasound-derived aortic strain parame...

## Key facts

- **NIH application ID:** 10804789
- **Project number:** 1I01BX006414-01
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** Jean Marie Ruddy
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10804789

## Citation

> US National Institutes of Health, RePORTER application 10804789, Targeting Biomechanical Signaling in AAA (1I01BX006414-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10804789. Licensed CC0.

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