{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T18:58:59Z","timestamp":1790276339220,"version":"4.1.0"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2026,9,25]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Peripheral artery occlusive disease (PAOD) is characterized by limb ischemia, heightened inflammation, and a substantial risk of mortality and amputation. Coordinated regulation of inflammation resolution and angiogenesis represents a promising therapeutic strategy. Given the established roles of FPRs (formyl peptide receptors) in inflammation resolution, we investigated their contribution to the integrated control of inflammation and angiogenesis in PAOD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Using a murine hindlimb ischemia model and clinical blood samples, we identified FPR1 as a key regulator of PAOD. We evaluated hindlimb perfusion recovery and inflammatory responses in\n                      <jats:italic toggle=\"yes\">Fpr1<\/jats:italic>\n                      -deficient mice. The therapeutic potential of an FPR1 agonist was assessed, and RNA sequencing was used to elucidate underlying mechanisms. FPR1\u2011dependent angiogenic responses were further confirmed in vivo using neutrophil\u2011specific\n                      <jats:italic toggle=\"yes\">Fpr1<\/jats:italic>\n                      -knockout mice and in vitro using neutrophils isolated from\n                      <jats:italic toggle=\"yes\">Fpr1<\/jats:italic>\n                      -deficient mice and individuals carrying the\n                      <jats:italic toggle=\"yes\">FPR1 rs867228<\/jats:italic>\n                      variant.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      We identified FPR1 as a pivotal regulator in PAOD.\n                      <jats:italic toggle=\"yes\">Fpr1<\/jats:italic>\n                      deficiency led to exaggerated inflammation and impaired angiogenesis, whereas FPR1 activation by a biased agonist, Cmpd17b, attenuated inflammation and improved perfusion recovery through a neutrophil\u2011dependent mechanism. Mechanistically, the Cmpd17b shifted neutrophil signaling away from Ca\n                      <jats:sup>2+<\/jats:sup>\n                      \u2011dependent proinflammatory pathways toward IL\u201110 (interleukin-10) and VEGF-A (vascular endothelial growth factor\u2011A) production. Further analysis revealed that FPR1 activation in neutrophils promotes CCL2 (C-C motif chemokine ligand 2) release, which may upregulate HMOX1 (heme oxygenase 1) in endothelial cells to enhance angiogenesis. We also demonstrated that\n                      <jats:italic toggle=\"yes\">FPR1 rs867228<\/jats:italic>\n                      confers protection in human PAOD by favoring pro-resolving responses and enhancing CCL2-mediated angiogenesis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>FPR1 is a central regulator of inflammation and angiogenesis in PAOD. Biased FPR1 activation engages a neutrophil\/CCL2-endothelial\/HMOX1 axis to resolve inflammation and promote angiogenesis, supporting its therapeutic potential in PAOD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.126.328454","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T09:00:17Z","timestamp":1787302817000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["FPR1-Driven Neutrophil-Endothelial Cell Axis Promotes Angiogenesis in PAOD"],"prefix":"10.1161","volume":"139","author":[{"given":"Fengyang","family":"Li","sequence":"first","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Shandong University, Jinan, China (F.L., Y.Z., X. Zhou, C.X.Q.)."},{"name":"Department of Emergency Medicine, Qilu Hospital, Shandong University, Jinan, China (F.L., Y.C., C.X.Q.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0185-0595","authenticated-orcid":true,"given":"Peishen","family":"Zhao","sequence":"additional","affiliation":[{"name":"Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (P.Z., O.L.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7494-8609","authenticated-orcid":true,"given":"Tianshu","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabology, Shandong Provincial Key Medical and Health Laboratory of Translational Medicine in Microvascular Aging, The First Affiliated Hospital of Shandong First Medical University &amp; Shandong Provincial Qianfoshan Hospital, Jinan, China (T.W., X. Zhou)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqin","family":"Zha","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Shandong University, Jinan, China (F.L., Y.Z., X. Zhou, C.X.Q.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinhao","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University &amp; Shandong Provincial Qianfoshan Hospital, Jinan, China (X. Zhao)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3759-1396","authenticated-orcid":true,"given":"Owen L.","family":"Woodman","sequence":"additional","affiliation":[{"name":"Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (P.Z., O.L.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9501-2546","authenticated-orcid":true,"given":"Yuguo","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Qilu Hospital, Shandong University, Jinan, China (F.L., Y.C., C.X.Q.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojun","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Shandong University, Jinan, China (F.L., Y.Z., X. Zhou, C.X.Q.)."},{"name":"Department of Endocrinology and Metabology, Shandong Provincial Key Medical and Health Laboratory of Translational Medicine in Microvascular Aging, The First Affiliated Hospital of Shandong First Medical University &amp; Shandong Provincial Qianfoshan Hospital, Jinan, China (T.W., X. Zhou)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2169-2686","authenticated-orcid":true,"given":"Cheng Xue","family":"Qin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Shandong University, Jinan, China (F.L., Y.Z., X. Zhou, C.X.Q.)."},{"name":"Department of Emergency Medicine, Qilu Hospital, Shandong University, Jinan, China (F.L., Y.C., 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