# Macrophage and Vascular Smooth Muscle Cell dialogue: role in aortic aneurysm

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $718,133

## Abstract

Project Summary
Abdominal aortic aneurysm (AAA) is a common vascular disorder associated with inflammation and upregulation
of matrix-metalloproteinases (MMP), which cause the local degradation of the extracellular matrix (ECM)
culminating in life-threatening rupture of the excessively damaged aortic wall. The incidence of AAA is
unacceptably high. Despite progress in primary preventive measures, AAA still accounts for > 13000 deaths
annually due to ruptured AAA in the United States. Because major knowledge gaps in the mechanisms that
contribute to sustained ECM degradation persist, there is currently no drug-based therapy to circumvent AAA,
surgery is the only alternative to overcome or delay the burden of patients. Previous work from our group has
identified an instrumental role for the neuronal guidance cue, netrin-1 in fostering vascular inflammation.
Transmural macrophage infiltration in the damaged vascular wall is a key hallmark of AAA. Their role in
sustaining ECM degradation in AAA remains poorly understood. The objective of this proposal is to characterize
the role of netrin-1 in sustaining ECM destruction in AAA. The central hypothesis is that macrophage-derived
netrin-1 is a pathological signal capable of fueling MMP activation in vascular smooth muscle cells (VSMC) and
the disruption of this cross-talk mechanism protects against pathological vascular remodeling in AAA. Our
rationale is based on important observations made during K99/R00 award that the absence of netrin-1 in
hematopoietic cells (Ntn1-/-) protects against AAA development and elastin fragmentation. Single cell RNA
sequencing revealed that netrin-1 was harbored in transmural macrophages. Importantly, RNA sequencing of
WT and Ntn1-/- aortas identified that MMP3 was downregulated in the VSMC in netrin-1-deficient mice. In our
specific aims, will use novel mouse models of tissue-specific or conditional deletion of netrin-1 in macrophages,
deletion of MMP3 and neogenin (the receptor of netrin-1) in VSMC to determine how this guidance cue
orchestrates a series of events that lead to sustained ECM degradation by fueling the supply of catalytic enzymes
to the abdominal tissue. The proposed research is innovative because we investigate the role netrin-1 in
mediating cross-talk startegies and deleterious vascular remodeling, a heretofore-unexamined mechanism in
AAA. Upon conclusion, we will understand the role of netrin-1 in synchronizing ECM damage via complex
mechanisms in AAA. This contribution is significant since we will test whether targeting netrin-1 after AAA is
established (inducible deletion murine models) can reverse the degradation of the ECM and prevent rupture. In
this translational approach, our data will pave the way for the development of promising preventive therapeutic
strategies aimed at targeting netrin-1 or antagonizing its signaling events to prevent AAA.

## Key facts

- **NIH application ID:** 9902522
- **Project number:** 5R01HL146627-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Bhama Ramkhelawon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $718,133
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9902522

## Citation

> US National Institutes of Health, RePORTER application 9902522, Macrophage and Vascular Smooth Muscle Cell dialogue: role in aortic aneurysm (5R01HL146627-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9902522. Licensed CC0.

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