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Platelet-derived serotonin links vascular disease and tissue fibrosis

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Item Type:Article
Title:Platelet-derived serotonin links vascular disease and tissue fibrosis
Creators Name:Dees, C. and Akhmetshina, A. and Zerr, P. and Reich, N. and Palumbo, K. and Horn, A. and Juengel, A. and Beyer, C. and Kroenke, G. and Zwerina, J. and Reiter, R. and Alenina, N. and Maroteaux, L. and Gay, S. and Schett, G. and Distler, O. and Distler, J.H.
Abstract: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 beta (TGF-beta)-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.
Keywords:5-HT2B Serotonin Receptor, Animal Disease Models, Blood Platelets, Extracellular Matrix, Fibroblasts, Fibrosis, Knockout Mice, Platelet Activation, Systemic Scleroderma, Serotonin, Signal Transduction, Transforming Growth Factor beta, Animals, Mice
Source:Journal of Experimental Medicine
Publisher:Rockefeller University Press
Page Range:961-972
Date:9 May 2011
Official Publication:https://doi.org/10.1084/jem.20101629
PubMed:View item in PubMed

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