Indoleacrylic acid mitigates vascular rarefaction and enhances ischemia-induced neovascularization in aging via APLNR signaling

The number of endothelial cells (ECs) decreases with aging; consequently, their function is impaired, which is a major cause of the mortality and morbidity of age-related ischemic diseases such as peripheral arterial disease (PAD). Growing evidence suggests that tryptophan metabolism dysfunction has been closely linked to age-related diseases and lifespan regulation across multiple species. In this study, we investigated whether tryptophan metabolism mediated vascular rarefaction and neovascularization impairment in aging. Fasting peripheral blood samples were collected from healthy volunteers, we found that the levels of indoleacrylic acid (IA), a metabolite primarily produced through gut microbial metabolism, were significantly lower in the elderly compared with the young. In both young and elderly PAD patients, lower IA levels were positively correlated with the PAD severity, risk of onset, and cardiovascular outcome, with larger correlation coefficients observed in the elderly patients. We established a hindlimb ischemia mouse model by ligating the femoral artery (FAL). A similar trend was observed between young and aged mice both non- and post-FAL. Supplementing aged mice with IA (50 mg·kg⁻¹·d⁻¹, i.g.) for 12 weeks was able to alleviate vascular dysfunction in aged mice. RNA-seq analysis revealed that IA activated the APLNR signaling pathway, alleviated ECs senescence, and enhanced their ability to respond to ischemia. These results provide new insights into the association between IA and vascular dysfunction, laying the theoretical foundation for the potential preventive and therapeutic roles of IA in age-related PAD.