FPR1-Driven Neutrophil-Endothelial Cell Axis Promotes Angiogenesis in PAOD.

BACKGROUND: 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. METHODS: 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 Fpr1-deficient mice. The therapeutic potential of an FPR1 agonist was assessed, and RNA sequencing was used to elucidate underlying mechanisms. FPR1‑dependent angiogenic responses were further confirmed in vivo using neutrophil‑specific Fpr1-knockout mice and in vitro using neutrophils isolated from Fpr1-deficient mice and individuals carrying the FPR1 rs867228 variant. RESULTS: We identified FPR1 as a pivotal regulator in PAOD. Fpr1 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‑dependent mechanism. Mechanistically, the Cmpd17b shifted neutrophil signaling away from Ca2+‑dependent proinflammatory pathways toward IL‑10 (interleukin-10) and VEGF-A (vascular endothelial growth factor‑A) 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 FPR1 rs867228 confers protection in human PAOD by favoring pro-resolving responses and enhancing CCL2-mediated angiogenesis. CONCLUSIONS: 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.