Background/Purpose: Systemic sclerosis (SSc) is a multisystem connective tissue disease characterized by fibrosis of the skin and certain internal organs due to the constitutive activation of fibroblasts following immune attacks and vascular injury. Although the pathogenesis of SSc still remains unknown, a variable degree of luminal thrombosis following vascular injury may contribute to impaired peripheral circulation and the activation of vascular cells and fibroblasts. Endothelial protein C receptor (EPCR) predominantly expressed on endothelial cells plays a critical role in the regulation of coagulation system and also mediates various cytoprotective effects by binding and activating protein C. Since the role of EPCR has not been studied in SSc, we here investigated the potential contribution of EPCR to the development of this disease by utilizing clinical samples and its animal models.

Methods: EPCR expression was examined in skin samples and cultivated dermal microvascular endothelial cells by immunostaining and/or quantitative reverse transcription PCR. Fli1 binding to the EPCR promoter was assessed by chromatin immunoprecipitation. Serum EPCR levels were determined by enzyme-linked immunosorbent assay in 65 SSc and 20 healthy subjects.

Results: EPCR expression was markedly decreased in dermal small vessels of SSc lesional skin compared with those of healthy control skin. Transcription factor Fli1, whose deficiency is implicated in SSc vasculopathy, occupied the EPCR promoter and EPCR expression was suppressed in Fli1 siRNA-treated human dermal microvascular endothelial cells and dermal small vessels of Fli1^+/- mice. In SSc patients, decreased serum EPCR levels were associated with diffuse skin involvement, interstitial lung disease and the current and past history of digital ulcers, all of which are associated with hyper-coagulation status. Furthermore, serum EPCR levels inversely correlated with plasma levels of plasmin-a2-plasmin inhibitor complex (PIC), suggesting that reduced expression of endothelial EPCR truly induces hyper-coagulation status in SSc. Moreover, circulating EPCR and PIC levels were normalized in parallel with the up-regulation of Fli1 and EPCR in endothelial cells after the treatment with bosentan, a potential disease modifying drug preventing the development of digital ulcers in SSc.

Conclusion: This is the first report demonstrating the potential contribution of reduced EPCR to the development of SSc. The present findings further reinforce the notions that endothelial Fli1 deficiency is a key feature underlying the induction of structural and functional abnormalities of SSc vasculopathy and that bosentan has a potential to reverse the vascular phenotype related to Fli1 deficiency. The reversal of impaired coagulation/fibrinolysis system is a possible mechanism underlying the preventive effect of bosentan on digital ulcers in SSc.

« Back to 2015 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/fli1-deficiency-contributes-to-the-downregulation-of-endothelial-protein-c-receptor-in-systemic-sclerosis-a-possible-role-in-pro-thrombotic-condition/