# Mechanistic studies of disease progression in aortic aneurysms

> **NIH VA I01** · VA CONNECTICUT HEALTHCARE SYSTEM · 2022 · —

## Abstract

Abdominal aortic aneurysm (AAA), a prevalent disease amongst veterans, affects more than 1 in 9
smokers and is responsible for 10,000 documented deaths every year in the US. AAA treatment remains
limited to surgical or endovascular repair for large aneurysms. This lack of an effective medical therapy reflects
existing gaps in knowledge regarding the molecular mechanisms of AAA, and lack of reliable tools for
evaluating vessel wall biology and monitoring therapeutic effectiveness in vivo. Several matrix
metalloproteinases (MMPs), including MMP-12 are upregulated in human AAA, and a number of MMPs have
been linked to AAA development. Elastin degradation is a key feature of aneurysm and MMP-12 is considered
the primary elastase in this setting. There are conflicting data regarding the role of MMP-12 in aneurysm
development and emerging information point to both anti- and pro-inflammatory functions for MMP-12 in
inflammatory disorders. This in conjunction with our preliminary data raise the intriguing hypothesis that MMP-
12 plays a dual role in aneurysm: inhibiting early stage aneurysm development through inhibition of neutrophil
recruitment to the vessel wall, and promoting expansion and rupture of established aneurysms by enhancing
vessel wall inflammation. Here, we introduce novel molecular imaging techniques for high resolution tracking of
vessel wall inflammation and MMP/MMP-12 imaging, which in conjunction with selective inhibitors and
knockout mice will be used to a) investigate the temporal and spatial pattern of MMP/MMP-12 activation in
relation to AAA development, progression and rupture; and b) address the role of MMP-12 in aneurysm.
Vascular remodeling will be tracked with high resolution multimodality molecular and structural imaging
followed by histomorphometric analysis in two complementary murine models, namely angiotensin II-induced
and calcium chloride-induced aneurysms. The temporal and spatial relationship between vessel wall biology,
response to therapy, and aneurysm expansion and rupture will be addressed through serial imaging in the
same animal. The effects of MMP-12 gene deletion and MMP-12 inhibition on aneurysm development, and
evolution of established aneurysms will be addressed. Combined, these studies will address novel aspects of
aneurysm pathobiology, validate novel therapeutic targets in preclinical models, and establish novel imaging
approaches for evaluation of vessel wall biology in aneurysms. Ultimately, this should lead to improved
management of patients with AAA (and possibly other vascular diseases); and reduce related morbidity,
mortality, and healthcare costs.

## Key facts

- **NIH application ID:** 10427154
- **Project number:** 5I01BX004038-04
- **Recipient organization:** VA CONNECTICUT HEALTHCARE SYSTEM
- **Principal Investigator:** MEHRAN M SADEGHI
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427154

## Citation

> US National Institutes of Health, RePORTER application 10427154, Mechanistic studies of disease progression in aortic aneurysms (5I01BX004038-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10427154. Licensed CC0.

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