Fibroblast activation protein mediates vascular restenosis after surgery for peripheral arterial disease

Abstract Postoperative vascular restenosis hampers long-term surgical outcomes in peripheral arterial disease (PAD). Aberrant vascular smooth muscle cell (VSMC) migration and proliferation drive neointimal hyperplasia, the core pathological feature of restenosis, yet key molecular regulators remain incompletely defined. This study characterizes fibroblast activation protein (FAP): GEO bioinformatics analyses nominated FAP as a candidate regulator. FAP is low in normal arteries but markedly upregulated in injured vessels and synthetic-phenotype VSMCs, correlating positively with VSMC migration. FAP knockdown represses VSMC migration in vitro and attenuates neointimal hyperplasia in vivo. RNA-sequencing implicates FAP in modulating the Net1–RhoA–ROCK axis, further validated by western blot. Collectively, FAP upregulation promotes VSMC migration to foster neointimal hyperplasia and restenosis, marking FAP as a potential biomarker and therapeutic target for PAD-associated restenosis.