# FGF12 induces aberrant mechanosignaling in aortic smooth muscle cells during thoracic aortic aneurysm formation in Marfan syndrome mice

## TL;DR

This study shows that FGF12 contributes to aortic problems in Marfan syndrome by disrupting cell signaling, and reducing FGF12 improves aortic health in mice.

## Contribution

FGF12 is identified as a novel mediator of mechanosignaling in aortic smooth muscle cells during thoracic aortic aneurysm formation in Marfan syndrome.

## Key findings

- FGF12 is upregulated in aortic smooth muscle cells of Marfan syndrome mice and patients.
- Reducing FGF12 levels in mice ameliorates aortic aneurysm formation and improves cell signaling.
- FGF12 activates the AngII/AT1R pathway, leading to increased cell stiffness and focal adhesion changes.

## Abstract

Marfan syndrome (MFS), caused by mutations in the FBN1 gene, predisposes individuals to thoracic aortic aneurysm (TAA), a life-threatening complication. Recent studies have suggested that dysregulated mechanosignaling in aortic smooth muscle cells (SMCs) plays a pivotal role in TAA pathogenesis in MFS. However, the key molecular drivers remain largely undefined. Here we identify fibroblast growth factor 12 (FGF12) as a novel mediator of aberrant mechanosignaling in aortic SMCs during TAA formation in MFS. FGF12 is markedly upregulated in aortic SMCs of thoracic aneurysmal aortas from Fbn1C1039G/+ MFS mice and from patients with MFS. Mechanistically, FGF12 expression is induced by transforming growth factor-β/SMAD signaling and by cyclic mechanical stretch in aortic SMCs. FGF12 upregulates the expression of angiotensin II (AngII) and AngII type 1 receptor (AT1R), thereby activating the AngII/AT1R signaling pathway. FGF12-induced AT1R activation promotes aberrant mechanosignaling, as indicated by increased RhoA-GTP levels, stress fiber formation, focal adhesion assembly and focal adhesion kinase phosphorylation, ultimately leading to increased aortic SMC stiffness. In vivo studies using Fgf12 heterozygous (Fgf12+/−) mice reveal that Fgf12 haploinsufficiency significantly ameliorates AngII/β-aminopropionitrile-induced TAA formation, accompanied by reduced AT1R signaling and attenuation of aberrant mechanosignaling in the thoracic aortas. Furthermore, in Fbn1C1039G/+ MFS mice, Fgf12 haploinsufficiency (Fgf12+/−Fbn1C1039G/+) substantially mitigates TAA progression and arterial stiffening, while alleviating dysregulated mechanosignaling in thoracic aortic SMCs. Collectively, these findings identify FGF12 as a critical regulator of aberrant mechanosignaling in aortic SMCs and a key contributor to TAA formation in MFS.

Marfan syndrome is a genetic disorder affecting connective tissue, often leading to dangerous aortic problems. This study explores how a protein called FGF12 might contribute to these issues. Researchers found that FGF12 is more active in the aortas of people with Marfan syndrome, which could worsen aortic problems. They used mice to study this further, focusing on how FGF12 affects cells in the aorta. The study involved experiments with mice and human cells to see how reducing FGF12 impacts aortic health. They discovered that lowering FGF12 levels in mice reduced the severity of aortic problems and improved cell function. This suggests that FGF12 plays a significant role in the development of aortic issues in Marfan syndrome. Researchers conclude that targeting FGF12 could be a promising way to treat or prevent these problems in people with Marfan syndrome.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.