# Vascular smooth muscle cell ferroptosis and abdominal aortic aneurysm

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $675,290

## Abstract

PROJECT SUMMARY/ABSTRACT
Abdominal aortic aneurysm (AAA) is a permanent abdominal aorta expansion with high mortality but limited
treatment options. Currently, there are no effective clinical medicines to prevent, delay, or reverse the growth
or rupture of AAA, except an open or endovascular surgical repair for symptomatic aneurysms or aneurysms at
high risk for rupture. Vascular smooth muscle cells (VSMC) are crucial in maintaining vascular wall integrity
and function, while VSMC depletion is a characteristic feature of AAA. Ferroptosis is a type of programmed cell
death dependent on iron and characterized by the accumulation of lipid peroxides. Smoking is a well-
established AAA risk factor, and cigarette smoke extract induces VSMC ferroptosis. Glutathione peroxidase 4
(GPX4) has been identified as a critical inhibitor of ferroptosis and apoptosis. Human genetics and Gene
Expression Omnibus database have demonstrated that decreased GPX4 expression is associated with an
increased risk of AAA. Our preliminary studies demonstrate that GPX4 is significantly reduced in the aorta of
AAA patients and animal models. Nicotine, a well-established AAA risk factor, reduced GPX4 and SMC
contractile protein expression. We posit that AAA risk factors can result in VSMC death via an
underappreciated pathway, i.e., ferroptosis in the artery resulting in AAA formation and rupture. We generated
VSMC-specific Gpx4 knockout mice (Gpx4SMKO) by crossing Myh11-Cre with Gpx4flox/flox mice. When
subjected to aneurysm induction by angiotensin II (Ang II) coupled with hypercholesterolemia, about 50% of
Gpx4SMKO mice died due to AAA rupture. The incidence rate and maximal diameters in Gpx4SMKO mice
were larger than in Gpx4flox/flox control mice. Specific Aim 1 will define the protective effects of VSMC-specific
GPX4 in AAA using our novel VSMC-selective GPX4 transgenic mice. We will also examine the effects of
VSMC-specific Gpx4 knockout using a different murine model with perivascular application of elastase, an AAA
model that does not produce rupture. Aim 2 will determine the GPX4-dependent protective mechanisms in
VSMC using gain- and loss-of-function strategies. We will examine the effects of GPX4 on AAA-relevant
stimuli-induced cell death, VSMC phenotypic switch, and inflammatory responses in primary human and
mouse abdominal aortic smooth muscle cells. Aim 3 will define that local activation of GPX4 attenuates AAA
pathogenesis by enhancing VSMC capacity of resistance to pathologic factors. Further, we will examine
whether the GPX4 activator protects against aneurysm development and rupture. Successful completion of the
proposed studies will establish novel mechanisms regulating VSMC loss and vascular inflammation in AAA,
which are likely to advance our understanding of the AAA formation and ultimately lead to novel strategies for
treating AAA.

## Key facts

- **NIH application ID:** 10879017
- **Project number:** 5R01HL166203-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Yanhong Guo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $675,290
- **Award type:** 5
- **Project period:** 2023-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879017

## Citation

> US National Institutes of Health, RePORTER application 10879017, Vascular smooth muscle cell ferroptosis and abdominal aortic aneurysm (5R01HL166203-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10879017. Licensed CC0.

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