Contribution to the peripheral vasculopathy and endothelial cell dysfunction by CXCL4 in Systemic Sclerosis

Abstract

Objective CXCL4, a chemokine with antiangiogenic property, is reported to be involved in systemic sclerosis (SSc) related pulmonary arterial hypertension (PAH). We investigated the contribution of CXCL4 to SSc development by focusing on the correlation of circulatory CXCL4 levels with their peripheral vasculopathy, as well as the effect of CXCL4 on endothelial cell dysfunction and angiogenesis disturbance in SSc and the potential signaling.MethodsWe measured the serum CXCL4 levels in 58 patients with SSc, 10 patients with the very early diagnosis of SSc (VEDOSS), and 80 healthy controls. Then, CXCL4 levels were correlated with their clinical features, especially the peripheral vasculopathy. These observations were further validated in an additional cohort including 50 SSc patients, 12 VEDOSS patients, and 80 healthy controls. Moreover, we studied the anti-angiogenesis effects and the underlying signaling of CXCL4 in human umbilical vein endothelial cells (HUVECs) in vitro. ResultsCirculating levels of the CXCL4 were 103.62% higher in patients with SSc and 201.51 % higher in patients with VEDOSS than matched HCs, and these observations were confirmed in two independent cohorts. CXCL4 levels were closely associated with digital ulcers (DU) and nailfold video capillaroscopy (NVC) abnormalities in SSc. The proliferation, migration, and tube formation of HUVECs were significantly inhibited by recombinant human CXCL4 or SSc derived serum, which reversed by CXCL4 neutralizing antibody, but not CXCR3 inhibitor. CXCL4 downregulated the transcription factor Friend leukaemia integration factor‐1 (Fli-1) via c-Abl signaling. Furthermore, CXCL4 blocked the transforming growth factor (TGF) -β or platelet-derived growth factor (PDGF) induced cell proliferation of HUVECs. Conclusions CXCL4 may contribute to peripheral vasculopathy in SSc by downregulating Fli-1 via c-Abl signaling in endothelial cells and interfering angiogenesis.