FGF18 aggravates angiotensin II-induced vascular smooth muscle cell dysfunction via the FGFR-ERK/AKT-GSK3β/β-catenin...

The development and progression of thoracic aortic aneurysm (TAA) are closely related to vascular smooth muscle cell (VSMC) apoptosis, oxidative stress, and phenotypic transformation. This study investigated the role of fibroblast growth factor 18 (FGF18) in angiotensin II (Ang II)-induced TAA and its underlying mechanisms.

An in vitro Ang II-induced VSMC injury model was established, and TAA-related candidate genes were screened from GSE83675 via bioinformatics analysis. VSMCs were subsequently treated with recombinant FGF18 or small interfering RNA targeting FGF18 (si-FGF18), and cell viability, apoptosis, reactive oxygen species (ROS) levels, and phenotypic markers were assessed. Activation of fibroblast growth factor receptor 2 (FGFR2)-extracellular signal-regulated kinase (ERK)/AKT-glycogen synthase kinase 3β (GSK3β)/β-catenin signaling was examined via subcellular fractionation, immunofluorescence, and T-cell factor (TCF)/lymphoid enhancer-binding factor (LEF) luciferase reporter assays. Pharmacological modulators, including the AKT activator SC79 and the β-catenin activator SKL2001, were used to validate pathway involvement.

Ang II induced dose-dependent apoptosis in VSMCs. Bioinformatics analysis identified FGF18 as an upregulated hub gene in TAA-related datasets, which was further confirmed in Ang II-treated VSMCs. Functional assays demonstrated that recombinant FGF18 aggravated Ang II-induced apoptosis, reduced cell viability, and enhanced oxidative stress, whereas FGF18 knockdown exerted protective effects. Moreover, FGF18 promoted phenotypic switching of VSMCs from a contractile to a synthetic state. Mechanistically, FGF18 activated the FGFR2-ERK/AKT signaling pathway, leading to the phosphorylation of GSK3β and subsequent nuclear translocation of β-catenin. Pharmacological activation of AKT or β-catenin reversed the inhibitory effects of FGF18 silencing.

FGF18 is upregulated in Ang II-induced TAA and promotes VSMC apoptosis, oxidative stress, and phenotypic transformation from a contractile to synthetic type by activating the FGFR-ERK/AKT-GSK3β/β-catenin signaling pathway, suggesting a potential role of FGF18 in TAA-associated vascular remodeling.