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 Fbn1 C1039G/+ 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 Fbn1 C1039G/+ MFS mice, Fgf12 haploinsufficiency ( Fgf12 +/− Fbn1 C1039G/+ ) 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.
Kim et al. (Fri,) studied this question.