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Contribution to the peripheral vasculopathy and endothelial cell dysfunction by CXCL4 in Systemic Sclerosis
Zhixing Jiang1, Chen Chen1, Sen Yang1
1Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China; Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China.
Insights
Elevated CXCL4 levels are linked to systemic sclerosis (SSc) complications like peripheral vasculopathy. This chemokine impairs endothelial cell function by downregulating Fli-1, contributing to SSc development.
Area of Science:
- Immunology
- Vascular Biology
- Rheumatology
Background:
- Chemokine CXCL4 (CXCL4) exhibits anti-angiogenic properties.
- CXCL4 is implicated in systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH).
Purpose of the Study:
- To investigate CXCL4's role in SSc pathogenesis.
- To correlate circulatory CXCL4 levels with peripheral vasculopathy in SSc.
- To examine CXCL4's effect on endothelial cell function and signaling.
Main Methods:
- Plasma CXCL4 levels measured in SSc patients, very early diagnosis of SSc (VEDOSS) patients, and healthy controls (HCs).
- CXCL4 levels correlated with clinical features, particularly peripheral vasculopathy.
- In vitro studies using human umbilical vein endothelial cells (HUVECs) assessed CXCL4's anti-angiogenic effects and signaling pathways.
Main Results:
- Significantly higher CXCL4 levels observed in SSc and VEDOSS patients compared to HCs.
- CXCL4 levels associated with digital ulcers and nailfold videocapillaroscopy abnormalities.
- CXCL4 inhibited HUVEC proliferation, migration, and tube formation, downregulating Friend leukaemia integration factor-1 (Fli-1) via c-Abl signaling.
Conclusions:
- CXCL4 contributes to SSc peripheral vasculopathy by downregulating Fli-1 in endothelial cells.
- CXCL4 interferes with angiogenesis, potentially exacerbating SSc.
- CXCL4 may be a therapeutic target for SSc-related vascular complications.
Background:
CXCL4, a chemokine with anti-angiogenic property, is involved in systemic sclerosis (SSc) related pulmonary arterial hypertension (PAH).
Objective:
To 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.
Methods:
We 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.
Results:
Circulating 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.
Conclusions:
CXCL4 may contribute to peripheral vasculopathy in SSc by downregulating Fli-1 via c-Abl signaling in endothelial cells and interfering angiogenesis.
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