Gain of function NOTCH4 variants disrupt angiogenesis in systemic sclerosis

Area of Science:

• Genetics
• Immunology
• Vascular Biology

Background:

• Systemic sclerosis (SSc) is characterized by vasculopathy and fibrosis, with unknown genetic factors contributing to severe disease, especially in African American (AA) populations.
• AA patients with SSc often exhibit more severe vascular phenotypes and poorer outcomes, necessitating investigation into underlying genetic causes.

Purpose of the Study:

• To investigate the genetic underpinnings of severe vasculopathy and adverse outcomes in African American patients with SSc.
• To explore the role of NOTCH4 in SSc pathogenesis and evaluate NOTCH4-directed therapies for vasculopathy.

Main Methods:

• Gene-based testing and exome-wide significance analysis identified NOTCH4 variants associated with SSc.
• Single-cell RNA sequencing, functional assays, and a mouse model were employed to study NOTCH4's role in endothelial-to-mesenchymal transition (EndoMT) and angiogenesis.
• Analysis included a specific risk haplotype enriched in AA patients and assessment of NOTCH4 inhibition strategies.

Main Results:

• NOTCH4 variants showed exome-wide significance for SSc and severe vascular disease in AA patients.
• A specific NOTCH4 risk haplotype was significantly enriched in AA patients with SSc, with a substantial population attributable risk.
• SSc-associated NOTCH4 variants increased NOTCH4 expression, leading to reduced angiogenesis and increased EndoMT; inhibition of NOTCH4 signaling rescued these effects.

Conclusions:

• NOTCH4 variants are implicated in SSc pathogenesis and vasculopathy, potentially explaining higher SSc prevalence and severity in AA individuals.
• Targeting the NOTCH4 pathway offers a potential therapeutic strategy for the vascular and fibrotic manifestations of SSc.
• Further research and clinical trials are warranted to explore NOTCH4 inhibition for SSc treatment.