Macrophage-Hypoxia-Inducible Factor-1α Signaling in Carotid Artery Stenosis

Macrophages play crucial and diverse roles in the pathogenesis of inflammatory vascular diseases. Macrophages are the principal innate immune cells recruited to arterial walls to govern vascular homeostasis by modulating the proliferation of vascular smooth muscle cells, the reorganization of extracellular matrix components, the elimination of dead cells, and the restoration of normal blood flow. However, chronic sterile inflammation within the arterial walls draws inflammatory macrophages into intimal/neointimal regions that may contribute to disease pathogenesis. In this context, the accumulation and aberrant activation of macrophages in the neointimal regions govern the progression of inflammatory arterial wall diseases. Herein, we report that myeloid-hypoxia-inducible factor-1 alpha (HIF1 alpha) deficiency attenuates vascular smooth muscle cells and macrophage abundance in stenotic arteries and abrogates carotid neointima formation in vivo. The integrated transcriptomics, Gene Set Enrichment Analysis, metabolomics, and target gene evaluation showed that HIF1 alpha represses oxidative phosphorylation, tricarboxylic acid cycle, fatty acid metabolism, and c-MYC signaling pathways while promoting inflammatory, glycolytic, hypoxia response gene expression in stenotic artery macrophages. At the molecular level, proinflammatory agents utilized STAT3 signaling pathways to elevate HIF1 alpha expression in macrophages. Collectively, this study uncovers that macrophage-HIF1 alpha deficiency restrains the pathogenesis of carotid artery stenosis by rewiring inflammatory and metabolic signaling pathways in macrophages.

Automated summary

Macrophages play crucial roles in inflammatory vascular diseases, and deficiency of HIF1α may attenuate vascular smooth muscle cells and macrophage abundance, reducing inflammation in stenotic arteries. HIF1α regulates various metabolic and inflammatory signaling pathways in macrophages.