A novel role for tryptophan and indoleamine 2,3 dioxygenase in human blood vessels

Indoleamine 2,3-dioxygenase 1 (IDO1), the first kynurenine pathway enzyme, catabolizes tryptophan and has been identified as critical regulator of vascular tone. Previous data are controversial on whether the mechanism of vasodilation by IDO1 is nitric oxide (NO) or H 2 O 2 -dependent, and evidence on a contribution of IDO1 in the human vasculature is very limited. Coronary artery disease (CAD) has been associated with inflammation and endothelial dysfunction, including a switch from NO- to H 2 O 2 -mediated vasodilation.We hypothesize that IDO1 contributes to the pathological switch from NO- to H 2 O 2 -mediated vasodilation in CAD. We aim to establish the role of IDO1 in dilation of human coronary and peripheral vessels from patients with CAD compared with healthy controls. We dissected arterioles (<300 micrometer) from human surgical discard tissues from patients with CAD and controls (≤1 cardiovascular risk factors). Vessels were cannulated onto two glass pipets and exposed to tryptophan (10 µM – 3 mM) or pressure gradient (5-100 mmHg) to induce flow mediated dilation (FMD) with and without the IDO1 inhibitor epacadostat (10 µM). Dilation is expressed as percentage of maximum diameter±SEM. Preliminary data suggest that tryptophan dilates coronary arteries from patients with CAD up to 55.9±15.7% at a concentration of 1 mM (n=4). At the same concentration, tryptophan-induced dilation seems to be significantly less pronounced in adipose arteries from patients with CAD (24.3±7.7%, n=4) and controls (12.9±7.6%, n=3). Interestingly, both CAD and control adipose arteries constricted to the highest concentration (3 mM) tryptophan. IDO1 inhibition may cause a slight reduction in flow-mediated dilation in adipose arteries from controls (from 82.1±4.5% to 69.9±24.4%, n≥2) and CAD patients (from 82.9±6.1% to 73.9±10.7%, n≥3). This study for the first time establishes that tryptophan dilates coronary arteries of patients with CAD, but that tryptophan-induced dilation is less pronounced in adipose arteries. Whether this dilation is dependent upon IDO1 and/or other mechanisms remains to be investigated. These preliminary data suggest that IDO1 may partly contribute to flow-induced vasodilation. Future research should determine whether tryptophan and IDO1 contribute to pathophysiological function of human arteries. If so, this may potentially open up new treatment strategies for CAD as well as other microvascular diseases. This research is supported by the Dutch Research Council (NWO), The Netherlands This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.