# Regulation of Cellular Phenotype Change in Thoracic Aortic Aneurysms

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2021 · —

## Abstract

Thoracic aortic aneurysms (TAAs) develop as a consequence to abnormal remodeling of the aortic extracellular
matrix (ECM).10 This usually asymptomatic process results in a weakened aortic wall manifested as gross
dilatation that progresses to rupture. Current treatment includes blood pressure management until the risk of
rupture outweighs the risk of surgical or endovascular intervention; neither of which address the underlying
pathways which drive this devastating disease.11 TAA development is influenced by a series of interrelated
mechanisms such as the matrix metalloproteinases (MMPs) 12-15, and dysregulation of the production and
deposition of ECM proteins.16 Importantly, these mechanisms are mediated in part through changes in the
resident cellular constituents within the aortic wall.17, 18 Transforming growth factor-beta (TGF-β), a soluble
peptide growth factor capable of regulating the structure and composition of the aortic ECM, is a well described
mediator of fibroblast phenotype.19 Current data shows that the alterations in TGF-β signaling result in a type-I
TGF-β receptor switch, from a TGF-β-R1 dominant signal, to an ALK-1 dominant signal. TGF-β is sequestered
within the extracellular matrix, bound by latent TGF-β binding proteins (LTBPs).21, 22 These latent complexes are
proteolytic targets for key MMPs, such as membrane type-I MMP (MT1-MMP), which is induced during TAA
development.8, 23 Results demonstrated that TAA development was attenuated in MT1-MMP heterozygous
deficient mice, and neutralizing antibody treatment targeting either TGF-β ligands (TGF-β-NAb) or MT1-MMP
activity (MT1-MMP-InhAb) was sufficient to attenuate aortic dilatation; suggesting MT1-MMP as an important
mediator of TAA formation and progression. New data demonstrate an increase in the number of mature
macrophages (F4/80+) at 8- and 16- weeks post-TAA induction; suggesting that macrophage-derived MT1-MMP
may also contribute to TAA development. The present proposal will explore the time-dependent and cell-type
specific expression of MT1-MMP using an established and well-characterized mouse model of TAA induction,
and several unique transgenic mouse strains. The central hypothesis of this study is that MT1-MMP-dependent
activation of TGF-β signaling is both time-dependent and cell-specific, and it will be tested through three specific
aims: (1) Demonstrate that fibroblast-derived MT1-MMP is required for TGF-β release and fibroblast
transdifferentiation, early in TAA development. Using a validated Tamoxifen-inducible, fibroblast-specific Cre-
dependent (Col1A2-Cre-ERT2) knockout of floxed-MT1-MMP, MT1-MMP will be deleted in fibroblasts prior to
TAA induction (Early), or after 4-weeks of TAA development (Late); (2) Demonstrate that macrophage-derived
MT1-MMP is required for TGF-β release and the maintenance of fibroblast phenotype, late in TAA development.
Using a Tamoxifen-inducible, monocyte/macrophage-specific Cre-dependent (LysM-Cre-ERT2) knockout of
floxed-MT1-...

## Key facts

- **NIH application ID:** 10265360
- **Project number:** 5I01BX000904-10
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** Jeffrey A. Jones
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2011-01-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10265360

## Citation

> US National Institutes of Health, RePORTER application 10265360, Regulation of Cellular Phenotype Change in Thoracic Aortic Aneurysms (5I01BX000904-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10265360. Licensed CC0.

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