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

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.