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

Abstract

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