This study discovered significantly elevated CCN1 and CCN2 expression in the skin and plasma of patients with antiphospholipid syndrome (APS) through single-cell RNA sequencing, revealing the critical role of the YAP1-CCN2 signaling axis in communication between microvascular endothelial cells and vascular smooth muscle cells. YAP1 nuclear translocation and high CCN2 expression were also observed in kidney tissues of APS patients. In a mouse model, anti-CCN2 monoclonal antibody effectively inhibited APS IgG-induced neointima formation, providing a novel therapeutic target for APS vasculopathy.
Literature Overview
This paper, titled 'Microvascular Endothelial Cells License APS Vasculopathy through YAP1- and CCN2-Mediated Signaling' and published in the journal 'Circulation', reviews and summarizes the molecular mechanisms of APS-related microvascular vasculopathy, particularly focusing on the signaling pathways between microvascular endothelial cells (MVEC) and vascular smooth muscle cells (VSMC). The research team used skin biopsies, plasma protein analysis, and mouse models to demonstrate the central role of YAP1 and CCN2 in APS vasculopathy, offering potential new therapeutic targets for clinical treatment.Background Knowledge
Antiphospholipid syndrome (APS) is an autoimmune disease characterized by persistently positive antiphospholipid antibodies (aPL), commonly associated with thrombosis and pregnancy complications. In addition to classical thrombotic manifestations, APS patients may develop microvascular vasculopathy, known as APS vasculopathy, which presents as small vessel occlusion in organs such as the skin, kidneys, and brain, leading to chronic tissue damage. Current APS treatments mainly rely on long-term anticoagulation, but these have limited efficacy against microvascular complications. The underlying mechanisms of APS vasculopathy remain incompletely understood, with previous studies suggesting a role for the mTORC pathway, but lacking comprehensive molecular insights. This study focuses on the skin due to its accessibility for biopsy and because APS skin lesions (e.g., livedo reticularis) reflect systemic microvascular pathology. The CCN family of proteins (e.g., CCN1/Cyr61, CCN2/CTGF) is known to regulate cell proliferation, adhesion, migration, and fibrosis, but their role in APS has not been previously reported. Through scRNA-seq, protein detection, and functional validation, this study systematically reveals the role of CCN2 in APS vasculopathy, providing a theoretical foundation for future targeted therapies.
Research Methods and Experiments
The study enrolled three APS patients with livedo reticularis and four healthy controls. Skin biopsies were performed, and MVECs were isolated for single-cell RNA sequencing (scRNA-seq). Gene expression analysis identified significant upregulation of CCN1 and CCN2 in APS MVECs. Immunofluorescence and ELISA were further used to validate CCN1/CCN2 expression in skin, kidney, and plasma. Healthy MVECs were stimulated with serum or IgG from APS patients, and qPCR, Western blot, and immunofluorescence were used to analyze signaling pathway activation. VSMCs were treated with conditioned media from APS IgG-stimulated MVECs to evaluate proliferation and migration. An APS IgG-induced neointima formation mouse model was developed, with some experiments including anti-CCN2 monoclonal antibody to assess its impact on vasculopathy.Key Conclusions and Perspectives
Research Significance and Prospects
This study is the first to demonstrate the activation of the YAP1-CCN2 signaling axis in APS microvascular vasculopathy, providing both in vitro and in vivo evidence for its role in MVEC-VSMC communication. The findings offer new mechanistic insights into APS vasculopathy and suggest CCN2 as a promising therapeutic target. Future studies should investigate the interactions of TLR4, YAP1, and EGFR in APS and evaluate the clinical potential of anti-CCN2 monoclonal antibodies. Additionally, CCN2 levels in APS patients may serve as a biomarker reflecting endothelial injury severity.
Conclusion
This study systematically uncovered the signaling crosstalk mechanism between MVECs and VSMCs in APS microvascular vasculopathy through multi-omics and functional analyses. IgG from APS patients activates YAP1 signaling in MVECs, leading to CCN2 upregulation, which in turn promotes VSMC proliferation and migration via EGFR. In a mouse model, anti-CCN2 monoclonal antibody effectively inhibited APS IgG-induced neointima formation, highlighting its therapeutic potential in APS-related vasculopathy. These findings provide new molecular insights into APS microvascular injury and lay the groundwork for future targeted therapies. While anti-CCN2 antibodies have entered clinical trials for diseases such as idiopathic pulmonary fibrosis, further validation is required for their application in APS. Moreover, due to the limited patient sample size in this study, larger cohorts are needed to evaluate the correlation between CCN2 levels and clinical features such as renal function and skin lesions. Overall, this study provides critical molecular clues for understanding APS microvascular injury mechanisms and opens new avenues for targeted therapeutic development.
