This study is the first to reveal the crucial role of the YAP1-CCN2 signaling axis in APS microvascular disease, offering new insights for targeted therapies. Using scRNA-seq, in vitro cell experiments, and mouse models, the research team discovered that CCN2 is significantly elevated in the plasma and microvascular endothelial cells of APS patients and can promote vascular smooth muscle cell proliferation and migration. These findings not only deepen our understanding of the molecular mechanisms underlying APS-related microvascular pathology but also provide theoretical support for the development of novel therapeutic strategies.
Literature Overview
This article, 'Microvascular endothelial cells license APS vasculopathy through YAP1- and CCN2-mediated signaling', published in Circulation, reviews and summarizes the interactive mechanisms between endothelial and smooth muscle cell signaling pathways in APS microvascular disease. Through single-cell RNA sequencing, immunofluorescence staining, ELISA, and mouse models, the study systematically revealed the expression profiles of CCN1 and CCN2 in APS patients, further exploring the role of YAP1 in regulating CCN2 expression. It also evaluated the therapeutic potential of anti-CCN2 antibodies in animal models, offering a new direction for the treatment of APS-related microvascular pathology.
Background Knowledge
Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombosis and microvascular pathology, with molecular mechanisms not yet fully understood. APS-related microvascular vasculopathy manifests as abnormal proliferation of endothelial and smooth muscle cells, leading to small vessel occlusion, commonly affecting organs such as the skin, kidneys, and brain. Currently, the main treatment for APS is lifelong anticoagulation, which has limited efficacy in addressing microvascular pathology. CCN family proteins, particularly CCN2 (CTGF), are well-documented for their roles in fibrosis, tissue repair, and angiogenesis. YAP1 (Yes-associated protein 1), a core effector of the Hippo signaling pathway, participates in processes like cell proliferation and migration, with its role in APS-related microvascular disease being reported for the first time. Utilizing single-cell sequencing, in vitro cell experiments, and mouse models, this study aimed to explore the molecular mechanisms of APS microvascular pathology and assess the therapeutic potential of CCN2. These findings lay the foundation for developing novel therapies targeting the YAP1-CCN2 axis.
Research Methods and Experiments
The study included skin biopsy samples from three APS patients with livedo racemosa and four healthy controls. Single-cell RNA sequencing (scRNA-seq) was used to analyze the gene expression profiles of skin microvascular endothelial cells (MVECs). Immunofluorescence and ELISA were further employed to validate the expression levels of CCN1 and CCN2. In vitro, healthy MVECs were exposed to serum or IgG from APS patients to assess changes in CCN1/CCN2 expression. siRNA was used to knock down YAP1, TLR4, or LRP8 to evaluate their influence on CCN2 expression. Finally, an accelerated APS IgG mouse model was established to assess the effect of an anti-CCN2 monoclonal antibody on neointima formation.
Key Conclusions and Perspectives
Research Significance and Prospects
This study provides new molecular targets for the targeted treatment of APS microvascular vasculopathy. Future work should further evaluate the expression dynamics of YAP1, CCN2, and EGFR in APS patients and explore the applicability of anti-CCN2 therapy across different organ microvascular pathologies. Additionally, the development of tissue-specific knockout mouse models will help validate the role of this signaling axis in different cell types.
Conclusion
This study systematically reveals the activation of the YAP1-CCN2 signaling pathway in APS microvascular vasculopathy and its functional role in MVEC-VSMC crosstalk. CCN2 levels are elevated in the plasma of APS patients, with expression positively correlating with renal dysfunction. In vitro and in vivo models demonstrated that anti-CCN2 antibodies effectively inhibit APS IgG-induced neointima formation. These findings not only provide a novel molecular mechanism explanation for APS-related microvascular disease but also suggest potential therapeutic targets, especially CCN2 and its receptor EGFR. Future studies should further validate the role of this signaling axis in other organs and explore its expression in non-APS populations.
