Zhang Qian, Zha Yuqin, Wang Xiaoting, Zhao Peishen, Woodman Owen L, Zhou Mi, Chen Yuguo, Zhou Xiaojun, Qin Cheng Xue
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
FASEB J. 2025 Sep 15;39(17):e71020. doi: 10.1096/fj.202501823R.
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.
下肢动脉疾病血管内介入治疗后的再狭窄会导致显著的发病率和死亡率。本研究调查了甲酰肽受体2（FPR2）在新生内膜增生中的作用，并评估了选择性FPR2激动剂BMS-986235在减轻再狭窄方面的治疗潜力。与健康对照相比，患有再狭窄的男性截肢者的腘动脉和胫前动脉中FPR2表达显著降低。在内皮损伤后，全身和骨髓特异性FPR2基因敲除小鼠始终表现出过度的新生内膜增生，并伴有血管腔直径明显减小。用BMS-986235治疗有效地减缓了再狭窄的进展。从机制上讲，FPR2激活维持了血管平滑肌细胞（VSMC）的分化状态，并限制了过量M2巨噬细胞的积累，从而限制了新生内膜重塑。转录组分析还确定ELOVL脂肪酸延长酶6（ELOVL6）是FPR2激活的一个新的下游靶点，其在再狭窄模型中上调。值得注意的是，BMS-986235降低了巨噬细胞和VSMC中ELOVL6的表达，抑制了VSMC增殖并减轻了新生内膜增生。FPR2激活通过FPR2/ELOVL6轴维持VSMC分化来减轻再狭窄进展，突出了其作为预防再狭窄新治疗靶点的潜力。
