FPR2 Agonism Attenuates Restenosis by Mitigating Neointimal Hyperplasia via ELOVL6

Restenosis following endovascular intervention in lower extremity arterial disease contributes to significant morbidity and mortality. This study investigates the role of formylpeptide receptor 2 (FPR2) in neointimal hyperplasia and evaluates the therapeutic potential of the selective FPR2 agonist BMS-986235 in mitigating restenosis. FPR2 expression was significantly reduced in the popliteal and anterior tibial arteries of male amputees with restenosis compared to healthy controls. Whole-body and myeloid-specific FPR2 knockout mice consistently displayed exaggerated neointimal hyperplasia, accompanied by a marked reduction in vessel lumen diameter, following endothelial injury. Treatment with BMS-986235 effectively slowed the progression of restenosis. Mechanistically, FPR2 activation maintained the differentiated state of vascular smooth muscle cells (VSMCs) and limited excessive M2 macrophages accumulation, thereby limiting neointimal remodeling. Transcriptomic analysis additionally identified ELOVL fatty acid elongase 6 (ELOVL6) as a novel downstream target of FPR2 activation, which was upregulated in restenosis models. Notably, BMS-986235 reduced ELOVL6 expression in both macrophages and VSMCs, inhibiting VSMC proliferation and mitigating neointimal hyperplasia. FPR2 activation mitigates restenosis progression by preserving VSMC differentiation through the FPR2/ELOVL6 axis, highlighting its potential as a novel therapeutic target for prevention of restenosis.