Factor Xa stimulates fibroblast procollagen production, proliferation, and calcium signaling via PAR1 activation

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 (PAR1). 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 PAR1-deficient mouse fibroblasts did not upregulate procollagen production, mobilize cytosolic calcium, or proliferate in response to factor Xa. Desensitization techniques and PAR1-specific agonists and inhibitors were used to demonstrate that PAR1 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 PAR1 and not PAR2. 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.

Protease-Activated Receptor-2 Induces Myofibroblast Differentiation and Tissue Factor Up-Regulation during Bleomycin-Induced Lung Injury

“…Indeed, both thrombin and FXa have been shown to have a proliferative effect on fibroblasts. 6,13,16,24 As shown in Figure 1C, BALF of IPF patients enhanced fibroblast survival by 40% as compared to BALF of controls. Strikingly, this increased viability induced by the BALF of IPF patients was significantly reduced by the FXa inhibitor TAP (to 21%), and by the thrombin inhibitor hirudin (to 8%).…”

A functional polymorphism (−603A → G) in the tissue factor gene promoter is associated with adult-onset asthma

“…32 In vivo activation of protease-activated receptors leads to proinflammatory responses, 33,34 bronchoconstriction 35 and airway remodeling. 36,37 The level of TF in the sputum is higher in asthma patients than in healthy controls. 5 The combined data suggest that TF might be involved in the pathogenesis of asthma through its participation in a number of different pathways.…”

Integrated effect of EGFR and PAR-1 signaling crosstalk on airway hyperresponsiveness

“…proliferation and collagen production (36). Accordingly, PAR-1 appears to be a new candidate factor for explaining the persistence of airway remodeling and the bronchoconstrictive response in asthmatic airways.…”