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

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.