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Factor Xa stimulates fibroblast procollagen production, proliferation, and calcium signaling via PAR(1) activation

Blanc-Brude, OP; Archer, F; Leoni, P; Derian, C; Bolsover, S; Laurent, GJ; Chambers, RC; (2005) Factor Xa stimulates fibroblast procollagen production, proliferation, and calcium signaling via PAR(1) activation. EXP CELL RES , 304 (1) 16 - 27. 10.1016/j.yexcr.2004.10.021.

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Abstract

Fibroblast proliferation and procollagen production are central features of tissue repair and fibrosis. In addition to its role in blood clotting, the coagulation cascade proteinase thrombin can contribute to tissue repair by stimulating fibroblasts via proteolytic activation of proteinase-activated receptor-1 (PAR(1)). During hemostasis, the coagulation cascade proteinase factor X is converted into factor Xa. We have previously shown that factor Xa upregulates fibroblast proliferation via production of autocrine PDGF. In this study, we further examined the effects of factor Xa on fibroblast function and aimed to identify its signaling receptor. We showed that factor Xa stimulates procollagen promoter activity and protein production by human and mouse fibroblasts. This effect was independent of PDGF and thrombin production, but dependent on factor Xa proteolytic activity. We also showed that PAR(1)-deficient mouse fibroblasts did not upregulate procollagen production, mobilize cytosolic calcium, or proliferate in response to factor Xa. Desensitization techniques and PAR(1)-specific agonists and inhibitors were used to demonstrate that PAR, mediates factor Xa signaling in human fibroblasts. This is the first report that factor Xa stimulates extracellular matrix production. In contrast with endothelial cells and vascular smooth muscle cells, fibroblasts appear to be the only cell type in which the effects of factor Xa are mediated mainly via PAR(1) and not PAR(2). These findings are critical for our understanding of tissue repair and fibrotic mechanisms, and for the design of novel approaches to inhibit the profibrotic effects of the coagulation cascade without compromising blood hemostasis. (C) 2004 Elsevier Inc. All rights reserved.

Type: Article
Title: Factor Xa stimulates fibroblast procollagen production, proliferation, and calcium signaling via PAR(1) activation
DOI: 10.1016/j.yexcr.2004.10.021
Keywords: fibroblast, coagulation, factor Xa, PAR(1), tissue repair, fibrosis, procollagen, proliferation, CELL PROTEASE RECEPTOR-1, COAGULATION-FACTOR-XA, THROMBIN RECEPTOR, GROWTH-FACTOR, PULMONARY-FIBROSIS, BRONCHOALVEOLAR LAVAGE, PROCOAGULANT ACTIVITY, LUNG FIBROBLASTS, TISSUE FACTOR, PROTEOLYTIC ACTIVATION
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine
URI: http://discovery.ucl.ac.uk/id/eprint/179506
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