Control of blood vessel tone is central to vascular homeostasis. Here we show that metabolism of tryptophan to kynurenine by indoleamine 2,3-dioxygenase (Ido) expressed in endothelial cells contributes to arterial vessel relaxation and the control of blood pressure. Infection of mice with malarial parasites (Plasmodium berghei) or induction of endotoxemia in mice led to endothelial expression of Ido, decreased plasma tryptophan concentration, increased kynurenine concentration and hypotension. Pharmacological inhibition of Ido increased blood pressure in systemically inflamed mice but not in mice deficient in Ido or interferon-γ, which is required for Ido induction. Both tryptophan and kynurenine dilated preconstricted porcine coronary arteries; the dilating effect of tryptophan required the presence of active Ido and an intact endothelium, whereas the effect of kynurenine was endothelium independent. The arterial relaxation induced by kynurenine was mediated by activation of the adenylate and soluble guanylate cyclase pathways. Kynurenine administration decreased blood pressure in a dose-dependent manner in spontaneously hypertensive rats. Our results identify tryptophan metabolism by Ido as a new pathway contributing to the regulation of vascular tone.
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We thank E. Andriambeloson, K. Choy, M. Finnemore, A. Mitchell and H. Salahifar for assistance and preliminary experiments, J. Whitworth for the suggestion to test the effect of kynurenine on blood pressure in spontaneously hypertensive rats, G. Head for advice on telemetry and B.H. Chong (University of New South Wales) for providing MEG-01 cells. This work was supported by project grants G03S1177 from the Australian National Heart Foundation to R.S., 400992 and 401106 from the National Health & Medical Research Council (NHMRC) of Australia to R.S., DP0987074 from the Australian Research Council to N.H.H. 512469 from the NHMRC to N.H.H. and National Heart Foundation (OS 98S0008) and Australian Research Council (DP0343325) fellowships to P.K.W. R.S. holds an NHMRC Senior Principal Research Fellowship and University of Sydney Medical Foundation and Professorial Research Fellowships.
The authors declare no competing financial interests.
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Wang, Y., Liu, H., McKenzie, G. et al. Kynurenine is an endothelium-derived relaxing factor produced during inflammation. Nat Med 16, 279–285 (2010). https://doi.org/10.1038/nm.2092
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