Downregulation of FLT1 delays vascular aging by suppressing MAPK signaling pathway activation in vascular smooth muscle cells​.

Vascular aging is a critical pathological basis of cardiovascular diseases (CVDs), involving functional abnormalities of vascular smooth muscle cells (VSMCs). This study investigated whether downregulation of Fms-related tyrosine kinase 1 (FLT1) ameliorates vascular aging by inhibiting the mitogen-activated protein kinase (MAPK) signaling pathway in VSMCs. Angiotensin II (Ang II) and bleomycin (Bleo) were used to induce VSMC senescence in vitro and establish a mouse aortic aging model in vivo. FLT1 was knocked down and overexpressed using small interfering RNA (siRNA) and pcDNA3.1 vectors, respectively. In vitro, cell proliferation was assessed by the Cell Counting Kit-8 assay and the 5-Ethynyl-2'-deoxyuridine incorporation assay, while senescence was evaluated through senescence-associated β-galactosidase (SA-β-gal) staining, gamma-H2A histone family member X (γ-H2AX) immunofluorescence (to assess DNA damage), and measurements of the nicotinamide adenine dinucleotide (NAD+/NADH) ratio. In vivo, vascular stiffness was assessed via pulse wave velocity (PWV), and aortic histopathology was examined using histological staining and immunohistochemistry. Additionally, Western blot analysis was performed to detect MAPK signaling pathway-related protein levels. Ang II and Bleo induced VSMC senescence in vitro (as evidenced by inhibited proliferation, increased SA-β-gal positivity, elevated DNA damage, and a reduced NAD+/NADH ratio) and promoted aortic aging in mice (characterized by elevated PWV, collagen deposition, and elastin degradation). FLT1 expression was upregulated in Ang II and Bleo-induced VSMCs and mouse aortic tissues. Downregulation of FLT1 alleviated VSMC and aortic aging while suppressing key proteins of the MAPK pathway, including p-ERK1/2 and p-p38 MAPK. Moreover, MAPK pathway inhibitors attenuated the pro-senescence effects of FLT1 overexpression in VSMCs and mouse aortas. Downregulation of FLT1 ameliorates VSMC and vascular aging by inhibiting the MAPK signaling pathway. These findings indicate a new treatment approach for CVDs related to aging. The online version contains supplementary material available at 10.1007/s10616-026-00947-3.