Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-48127
Dees, C; Akhmetshina, A; Zerr, P; Reich, N; Palumbo, K; Horn, A; Jüngel, A; Beyer, C; Krönke, G; Zwerina, J; Reiter, R; Alenina, N; Maroteaux, L; Gay, S; Schett, G; Distler, O; Distler, J H W (2011). Platelet-derived serotonin links vascular disease and tissue fibrosis. Journal of Experimental Medicine, 208(5):961-972.
Vascular damage and platelet activation are associated with tissue remodeling in diseases such as systemic sclerosis, but the molecular mechanisms underlying this association have not been identified. In this study, we show that serotonin (5-hydroxytryptamine [5-HT]) stored in platelets strongly induces extracellular matrix synthesis in interstitial fibroblasts via activation of 5-HT(2B) receptors (5-HT(2B)) in a transforming growth factor β (TGF-β)-dependent manner. Dermal fibrosis was reduced in 5-HT(2B)(-/-) mice using both inducible and genetic models of fibrosis. Pharmacologic inactivation of 5-HT(2B) also effectively prevented the onset of experimental fibrosis and ameliorated established fibrosis. Moreover, inhibition of platelet activation prevented fibrosis in different models of skin fibrosis. Consistently, mice deficient for TPH1, the rate-limiting enzyme for 5-HT production outside the central nervous system, showed reduced experimental skin fibrosis. These findings suggest that 5-HT/5-HT(2B) signaling links vascular damage and platelet activation to tissue remodeling and identify 5-HT(2B) as a novel therapeutic target to treat fibrotic diseases.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Rheumatology Clinic and Institute of Physical Medicine|
04 Faculty of Medicine > Center for Integrative Human Physiology
|DDC:||570 Life sciences; biology|
610 Medicine & health
|Deposited On:||23 May 2011 16:26|
|Last Modified:||23 Nov 2012 17:45|
|Publisher:||Rockefeller University Press|
|Additional Information:||Copyright: the Authors|
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