Macrophage IL-1β promotes arteriogenesis by autocrine STAT3-and NF-κB-mediated transcription of pro-angiogenic VEGF-A

Peripheral artery disease (PAD) leads to considerable morbidity, yet strategies for therapeutic angiogenesis fall short of being impactful. Inflammatory macrophage subsets play an important role in orchestrating post-developmental angiogenesis, but the underlying mechanisms are unclear. Here, we find that macrophage VEGF-A expression is dependent upon the potent inflammatory cytokine, IL-1 beta. IL-1 beta promotes pro-angiogenic VEGF-A(165)a isoform transcription via activation and promoter binding of STAT3 and NF-kappa B, as demonstrated by gene-deletion, gain-of-function, inhibition, and chromatin immunoprecipitation assays. Conversely, IL-1 beta-deletion or inhibition of STAT3 or NF-kappa B increases anti-angiogenic VEGF-A(165)b isoform expression, indicating IL-1 beta signaling may also direct splice variant selection. In an experimental PAD model of acute limb ischemia, macrophage IL-1 beta expression is required for pro-angiogenic VEGF-A expression and for VEGF-A-induced blood flow recovery via angio- or arteriogenesis. Though further study is needed, macrophage IL-1 beta-dependent transcription of VEGF-A via STAT3 and NF-kappa B may have potential to therapeutically promote angiogenesis in the setting of PAD.

Automated summary

IL-1β in inflammatory macrophages activates STAT3 and NF-κB to promote VEGF-A transcription, thereby facilitating angiogenesis. Macrophage IL-1β expression is crucial for blood flow recovery in a PAD model.