# Browning of perivascular adipose tissue protects against thoracic aortic aneurysm

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $586,229

## Abstract

PROJECT SUMMARY/ABSTRACT
Thoracic aortic aneurysm (TAA) is a life-threatening disease and has a high mortality rate if rupture occurs.
Currently, apart from endovascular or open surgery repair, no drug has been demonstrated to be effective for
TAA treatment. Even though some patients with TAA have evidence of a heritable aortopathy, about 75% of
TAA patients have severe aortic damage without a clear genetic etiology. The scant mechanistic knowledge is
limiting the development of medications for the treatment of TAA, thus highlighting a pressing need for better
understanding TAA formation and progression. Aorta is naturally surrounded by perivascular adipose tissue
(PVAT). Recent large-scale epidemiological studies demonstrated that PVAT was highly associated with a
significantly higher adjusted risk of all-cause cardiac mortality. We and others documented that brown-like
PVAT contributes to vascular homeostasis in health, while whitening of PVAT is dysfunctional and contributes
to development of the vascular diseases. A causal relationship between PVAT and TAA and the underlying
mechanisms remain unknown. Our preliminary studies indicate that the PVAT near the TAA lesion in patients
lost brown characteristics, and that TAA formation was dramatically increased in mice that lack normal PVAT,
suggesting that dysfunctional PVAT is associated with TAA. The conditioned medium from PVAT of TAA
patients induced apoptosis and inflammation in human aortic smooth muscle cells, suggesting that signaling
from PVAT can cause loss of vascular smooth muscle cells (VSMC) in the aorta, which may promote TAA
lesion. It is unknown whether browning of PVAT could protect against TAA. PR-domain containing 16
(PRDM16) is a determinant of browning gene programs. We show that PRDM16 expression in PVAT of TAA
patients is significantly reduced when compared to that in normal PVAT. PRDM16 inhibited resistin expression
in PVAT. We found that nitrated conjugated linoleic acid (NO2-CLA) induced the browning of human PVAT
adipocytes by mediating PRDM16 signaling. Based on these data, we hypothesize that PRDM16-mediated
PVAT browning prevents TAA formation. We will determine that 1) PRDM16 in PVAT prevents and reverses
TAA in mice; 2) PRDM16 inhibits TAA by regulating PVAT crosstalk with VSMC; 3) NO2-CLA prevents TAA by
targeting PRDM16. Outcomes will demonstrate that a previously unrecognized process involving loss of
browning features in PVAT promotes TAA formation through crosstalk to VSMC. This work will accelerate
clinical translation of a nitro-fatty acid-based treatment for TAA targeting PVAT homeostasis with this new
class of drugs, currently on clinical trials for other diseases.

## Key facts

- **NIH application ID:** 10462357
- **Project number:** 1R01HL159871-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** YUQING Eugene CHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $586,229
- **Award type:** 1
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10462357

## Citation

> US National Institutes of Health, RePORTER application 10462357, Browning of perivascular adipose tissue protects against thoracic aortic aneurysm (1R01HL159871-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10462357. Licensed CC0.

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