Interleukin‐ 17F Induces Ischemic Injury in Aged Mice by Causing Endothelial Cells' Senescence and Dysfunction

ABSTRACT This study investigated the relationship between plasma Interleukin‐17A (IL‐17A) and Interleukin‐17F (IL‐17F) levels and peripheral arterial disease (PAD), and explored the role of IL‐17F in neovascularization in a preclinical PAD model of aged mice. Using an enzyme‐linked immunosorbent assay, we found that plasma IL‐17A levels were similar in young and aged groups in both PAD patients and mice with hindlimb ischemia. In contrast, IL‐17F levels were elevated in the aged group. Spearman correlation analysis showed a positive correlation between IL‐17F levels and PAD severity, onset risk, and cardiovascular outcome. Under simulated ischemic conditions, IL‐17F induced endothelial cells (ECs) senescence and dysfunction in a dose‐dependent manner. In aged male and female mice following left femoral artery ligation, results from Doppler imaging, ischemia and motor scores, and histology indicated that neutralization of IL‐17F enhanced blood flow recovery, reduced ischemia scores, improved motor scores, and facilitated muscle regeneration and repair. Micro‐CT, whole‐mounting, and immunofluorescence staining results showed that neutralization of IL‐17F promoted neovascularization and inhibited ischemic hindlimb muscle ECs' senescence and dysfunction. This study reveals for the first time that higher IL‐17F levels were positively associated with PAD severity, onset risk, and cardiovascular outcome. Neutralization of IL‐17F promoted postischemic neovascularization in aged mice, suggesting it represented a promising therapeutic strategy for elderly PAD patients.