Email updates

Keep up to date with the latest news and content from BMC Pharmacology and BioMed Central.

This article is part of the supplement: 4th International Conference of cGMP Generators, Effectors and Therapeutic Implications

Open Access Oral presentation

Kynurenine is a novel endothelium-derived vascular relaxing factor produced during inflammation

Yutang Wang1, Hanzhong Liu2, Gavin McKenzie2, Paul K Witting1, Johannes-Peter Stasch3, Michael Hahn3, Katherine A Jackman4, Dechaboon Changsirivathanathamrong1, Ben J Wu2, Helen J Ball1, Shane R Thomas2, David S Celermajer5, Andrew L Mellor6, Chris G Sobey4, John F Keaney7, Nicholas H Hunt1 and Roland Stocker1*

Author Affiliations

1 University of Sydney, Bosch Institute, Sydney, Australia

2 University of New South Wales, School of Medical Sciences, Sydney, Australia

3 Bayer HealthCare, Wuppertal, Germany

4 Monash University, Department of Pharmacology, Melbourne, Australia

5 Royal Prince Alfred Hospital, Sydney, Australia

6 Immunotherapy Center, Medical College of Georgia, Augusta GA, USA

7 University of Massachusetts Medical School, Worcester MA, USA

For all author emails, please log on.

BMC Pharmacology 2009, 9(Suppl 1):S39  doi:10.1186/1471-2210-9-S1-S39


The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2210/9/S1/S39


Published:11 August 2009

© 2009 Wang et al; licensee BioMed Central Ltd.

Background

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.

Methods

We used three models of inflammation: infection of mice with malarial parasites (Plasmodium berghei), LPS-induced endotoxemia, and transient cerebral ischemia (stroke model). Blood pressure was determined via tail-cuff, and vascular function studies carried out in wire bath systems. IDO expression and activity were assessed by IHC and HPLC, respectively.

Results

All models of inflammation caused expression of IDO in micro-vascular endothelial cells, resulting in decreased plasma tryptophan and increased kynurenine. In malaria infection and endotoxemia, IDO expression was associated with hypotension. Pharmacological inhibition of IDO increased blood pressure in systemically inflamed mice, but not in mice deficient for IDO or interferon-γ, which is required for IDO induction. In endotoxemic mice, IDO deficiency partially attenuated the observed hypotension. In experimental stroke, total infarct volume was similar, yet cortical infarct volume was 4-fold greater in IDO KO than WT mice, consistent with IDO enhancing collateral blood flow. In functional studies, the IDO substrate tryptophan dilated pre-constricted arteries only if active IDO and an intact endothelium were present, whereas the IDO product kynurenine relaxed pre-constricted rings independent of an intact endothelium. Mechanistic studies revealed kynurenine to relax arteries via activation of soluble guanylate cyclase.

Conclusion

This study reveals IDO-mediated tryptophan metabolism to kynurenine as a previously unrecognized and important pathway contributing to the regulation of vascular tone in the setting of inflammation.