# Dedicator of cytokinesis 2 in abdominal aortic aneurysm

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2022 · $523,201

## Abstract

Summary/Abstract
Abdominal aortic aneurysm (AAA) is a potentially lethal disease that lacks pharmacological treatment. Aortic wall
inflammation and subsequent degradation of extracellular matrix (ECM) proteins, especially the elastin breakage,
are the determining factors for the development of AAA. Vascular inflammation, particularly macrophage
infiltration and inflammatory SMC phenotype, causes the production of proteolytic enzymes that disrupt ECM
homeostasis leading to a weakened vessel wall and consequently AAA formation. However, there is a critical
knowledge gap concerning the mechanism(s) or key factor(s) controlling both the vascular inflammation and the
ECM dysregulation. Our exciting preliminary data indicate that dedicator of cytokinesis 2 (DOCK2) plays a
central role in the induction of inflammatory SMC phenotype and AAA formation. DOCK2 deficiency (DOCK2-/-)
in mice significantly attenuates AAA formation (with decreased elastin breakage and improved artery wall
integrity) and diminishes the induction of inflammatory SMC phenotype. Consequently, DOCK2-/- inhibits the
expression of monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-2 (MMP2) in SMCs
while restoring contractile SMC markers. Consistently, the macrophage infiltration in aneurysm arterial media is
blocked in DOCK2-/- mice. Moreover, DOCK2 expression is associated with aneurysm formation in human
patients. These data strongly support a novel hypothesis that DOCK2 induces inflammatory SMC phenotype
leading to vascular inflammation, elastin breakage, and consequently AAA formation. Using primary mouse and
human SMCs, in vivo DOCK2 SMC-, macrophage-, and T cell- specific knockout mouse models combining with
molecular, cellular, histological, and pharmacological approaches, we will 1) determine the mechanisms by
which DOCK2 regulates inflammatory SMC phenotype; and 2) test the hypothesis that DOCK2 promotes AAA
formation by stimulating inflammatory SMC phenotype in vivo. Successful completion of the proposed studies
will establish novel mechanisms regulating SMC inflammatory phenotype and vascular inflammation, which are
likely to advance our understanding of the AAA formation and ultimately lead to novel strategies for developing
effective therapeutics to treat AAA.

## Key facts

- **NIH application ID:** 10417112
- **Project number:** 5R01HL147313-05
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** Shiyou Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $523,201
- **Award type:** 5
- **Project period:** 2019-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10417112

## Citation

> US National Institutes of Health, RePORTER application 10417112, Dedicator of cytokinesis 2 in abdominal aortic aneurysm (5R01HL147313-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10417112. Licensed CC0.

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