Abstract
BackgroundCXCL4, a chemokine with anti-angiogenic property, is involved in systemic sclerosis (SSc) related pulmonary arterial hypertension (PAH). ObjectiveTo investigated the contribution of CXCL4 to SSc development by focusing on the correlation of circulatory CXCL4 levels with their peripheral vasculopathy, and the effect of CXCL4 on endothelial cell dysfunction and the potential signaling. MethodsWe measured the plasma CXCL4 levels in 58 patients with SSc, 10 patients with the very early diagnosis of SSc (VEDOSS), and 80 healthy controls (HCs). Then, CXCL4 concentrations were correlated with clinical features, especially the peripheral vasculopathy. These observations were further validated in an additional cohort. Moreover, we studied the anti-angiogenic effects of CXCL4 and the underlying downstream signaling in human umbilical vein endothelial cells (HUVECs) in vitro. ResultsCirculating CXCL4 levels were 103.62 % higher in patients with SSc and 201.51 % higher in patients with VEDOSS than matched HCs, which were confirmed in two independent cohorts. CXCL4 levels were associated with digital ulcers (DU) and nailfold videocapillaroscopy (NVC) abnormalities in SSc. The proliferation, migration, and tube formation of HUVECs were inhibited by CXCL4 or SSc derived plasma, which reversed by CXCL4 neutralizing antibody, but failed by 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. ConclusionsCXCL4 may contribute to peripheral vasculopathy in SSc by downregulating Fli-1 via c-Abl signaling in endothelial cells and interfering angiogenesis.
Highlights
Systemic sclerosis (SSc) is an autoimmune disease with skin and multiple viscera involvement, which characterized by a complex interplay of vasculopathy, immune system activation, and persistent tissue fibrosis[1]
Circulating levels of the CXCL4 were 103.62% higher in patients with systemic sclerosis (SSc) and 201.51 % higher in patients with very early diagnosis of SSc (VEDOSS) than matched healthy controls (HCs), and these observations were confirmed in two independent cohorts
The proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) were significantly inhibited by recombinant human CXCL4 or SSc derived serum, which reversed by CXCL4 neutralizing antibody, but not CXCR3 inhibitor
Summary
Systemic sclerosis (SSc) is an autoimmune disease with skin and multiple viscera involvement, which characterized by a complex interplay of vasculopathy, immune system activation, and persistent tissue fibrosis[1]. Progressive and marked reduction in capillaries is a hallmark finding in early stage SSc with avascularity increasing with disease progression. Patients with SSc may develop a spectrum of vascular disease, mainly including Reynaud’s phenomenon (RP), digital ulcer (DU), pulmonary arterial hypertension (PAH), and scleroderma renal crisis (SRC). As the first onset symptom, RP leads to continuous digital ischemia, which may develop into digital ulcers (DU) or severe digital ischemia with gangrene in some extreme cases[3]. These early events induce increasing vascular tone, decreasing capillary blood flow, and chronic tissue hypoxia, leading to the extracellular matrix (ECM)[4] accumulation and tissue fibrosis. It is necessary to identify biomarkers that could predict the very early SSc, before inevitable organ injury and fibrosis occurred
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