FPR1-Driven Neutrophil-Endothelial Cell Axis Promotes Angiogenesis in PAOD.
basic_science · Level V
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- Record sourced from PubMed, PMID 42626783.
- Also identified by DOI 10.1161/CIRCRESAHA.126.328454.
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Abstract
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. 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 <i>Fpr1</i>-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 <i>Fpr1</i>-knockout mice and in vitro using neutrophils isolated from <i>Fpr1</i>-deficient mice and individuals carrying the <i>FPR1 rs867228</i> variant. We identified FPR1 as a pivotal regulator in PAOD. <i>Fpr1</i> 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 Ca<sup>2+</sup>‑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 <i>FPR1 rs867228</i> confers protection in human PAOD by favoring pro-resolving responses and enhancing CCL2-mediated angiogenesis. 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.