IDO1 improves postischemic neovascularization in aged mice by boosting endothelial NAD(+) de novo synthesis and curbing endothelial senescence.

INTRODUCTION: Peripheral arterial disease (PAD) is prevalent among the elderly, and therapeutic neovascularization is a research hotspot in PAD treatment. Supplementing nicotinamide adenine dinucleotide (NAD(+)) precursors is an important approach for promoting neovascularization, but clinical trials in the elderly PAD patients have shown limited success. This study aims to find effective ways to boost NAD(+) levels in elderly PAD patients to enhance neovascularization. METHODS: Transcriptome and NAD(+)-targeted metabolomics analyses were conducted on ischemic hindlimb muscle endothelial cells (ECs). The role of indoleamine 2,3-dioxygenase 1 (IDO1) in postischemic neovascularization was studied using global knockout mice. Mechanisms regulating IDO1 expression were investigated through transcriptomics and functional experiments. The effects of IDO1 protein on postischemic neovascularization were evaluated in vivo and in vitro. Plasma IDO1 levels were measured in young and elderly PAD patients and correlated with clinical indicators of PAD. RESULTS: In aged mice, ECs exhibited decreased NAD(+) de novo synthesis and IDO1 transcription. IDO1 deficiency induced the decline of ECs NAD(+) de novo synthesis and ECs senescence, impaired neovascularization in young mice. Elevated IL-17A/F inhibited IDO1 transactivation via CREB, impairing neovascularization. IDO1 administration alleviated the decline of ECs NAD(+) de novo synthesis and ECs senescence, and enhanced neovascularization in aged mice. Plasma IDO1 levels were lower in elderly PAD patients, correlating positively with disease severity, onset risk, and cardiovascular outcomes. CONCLUSION: ECs NAD(+) metabolism imbalance is driven by decreased de novo synthesis of NAD(+) and targeting IDO1 to elevate NAD(+) levels could be a potential therapeutic direction for elderly PAD patients.