Qian Zhang, Yuqin Zha, Xiaoting Wang, Peishen Zhao, Owen L. Woodman, Mi Zhou, Yuguo Chen, Xiaojun Zhou, Cheng Xue Qin
{"title":"FPR2激动作用通过ELOVL6减轻内膜增生减轻再狭窄","authors":"Qian Zhang, Yuqin Zha, Xiaoting Wang, Peishen Zhao, Owen L. Woodman, Mi Zhou, Yuguo Chen, Xiaojun Zhou, Cheng Xue Qin","doi":"10.1096/fj.202501823R","DOIUrl":null,"url":null,"abstract":"<p>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.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2000,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501823R","citationCount":"0","resultStr":"{\"title\":\"FPR2 Agonism Attenuates Restenosis by Mitigating Neointimal Hyperplasia via ELOVL6\",\"authors\":\"Qian Zhang, Yuqin Zha, Xiaoting Wang, Peishen Zhao, Owen L. Woodman, Mi Zhou, Yuguo Chen, Xiaojun Zhou, Cheng Xue Qin\",\"doi\":\"10.1096/fj.202501823R\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>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.</p>\",\"PeriodicalId\":50455,\"journal\":{\"name\":\"The FASEB Journal\",\"volume\":\"39 17\",\"pages\":\"\"},\"PeriodicalIF\":4.2000,\"publicationDate\":\"2025-09-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501823R\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The FASEB Journal\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202501823R\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The FASEB Journal","FirstCategoryId":"99","ListUrlMain":"https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202501823R","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
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.
期刊介绍:
The FASEB Journal publishes international, transdisciplinary research covering all fields of biology at every level of organization: atomic, molecular, cell, tissue, organ, organismic and population. While the journal strives to include research that cuts across the biological sciences, it also considers submissions that lie within one field, but may have implications for other fields as well. The journal seeks to publish basic and translational research, but also welcomes reports of pre-clinical and early clinical research. In addition to research, review, and hypothesis submissions, The FASEB Journal also seeks perspectives, commentaries, book reviews, and similar content related to the life sciences in its Up Front section.