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Gain of function NOTCH4 variants disrupt angiogenesis in systemic sclerosis
Urvashi Kaundal1, Pei-Suen Tsou2, Mousumi Sahu1
1Scleroderma Genomics and Health Disparities Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Insights
Genetic variants in NOTCH4 are linked to systemic sclerosis (SSc) vasculopathy, particularly in African American patients. Inhibiting NOTCH4 signaling shows promise for treating SSc vascular and fibrotic complications.
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.
Objectives:
Vasculopathy and fibrosis are central to the pathogenesis of systemic sclerosis (SSc) and their genetic underpinnings are largely unknown. Here, we sought to examine the aetiology of severe vascular phenotypes and poorer outcomes in African American (AA) patients with SSc.
Methods:
The study focuses on AA patients with SSc who have more severe vascular phenotypes and poorer outcomes and combines genetics, single-cell RNA sequencing, functional assays, and a mouse model to explore the role of NOTCH4 in SSc vasculopathy and the potential for NOTCH4-directed therapies.
Results:
Gene-based testing identified NOTCH4 association at an exome-wide significance with SSc (P = 1.6 × 10-7) and patients with severe vascular disease (P = 3.5 × 10-7). The risk haplotype defined by the missense (c.2824C>T) and promoter (c.-117G>A) variants was enriched in AAs with SSc (11%) vs controls, and the population attributable risk due to this haplotype in AAs with SSc was 2.6%, which was 52-fold higher than in European Americans. The SSc-associated NOTCH4 variants increased NOTCH4 expression and signalling, leading to decreased angiogenesis and increased endothelial-to-mesenchymal transition (EndoMT). Nailfold capillary abnormalities, decreased angiogenesis, and fibrosis of the vascular lumen are commonly seen in SSc. Genetic, chemical, antibody, or Food and Drug Administration-approved drug inhibition of NOTCH4 signalling rescued angiogenesis and returned EndoMT to baseline.
Conclusions:
NOTCH4 variants are associated with SSc pathogenesis and vasculopathy, partly explaining the increased prevalence of SSc in AAs. The study highlights the need for further research and clinical trials in the inhibition of the NOTCH4 pathway as a strategy to treat the vascular and fibrotic manifestations of SSc.
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