Downregulation of the transforming growth factor-β/connective tissue growth factor 2 signalling pathway in venous malformations: its target potential for sclerotherapy
J.-G. Ren
The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
Search for more papers by this authorCorresponding Author
G. Chen
The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, China
Correspondence
Gang Chen and Yi-Fang Zhao.
E-mails:[email protected] and [email protected]
Search for more papers by this authorJ.-Y. Zhu
The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
Search for more papers by this authorW. Zhang
The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
Search for more papers by this authorY.-F. Sun
The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, China
Search for more papers by this authorJ. Jia
The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, China
Search for more papers by this authorJ. Zhang
The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
Search for more papers by this authorCorresponding Author
Y.-F. Zhao
The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, China
Correspondence
Gang Chen and Yi-Fang Zhao.
E-mails:[email protected] and [email protected]
Search for more papers by this authorJ.-G. Ren
The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
Search for more papers by this authorCorresponding Author
G. Chen
The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, China
Correspondence
Gang Chen and Yi-Fang Zhao.
E-mails:[email protected] and [email protected]
Search for more papers by this authorJ.-Y. Zhu
The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
Search for more papers by this authorW. Zhang
The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
Search for more papers by this authorY.-F. Sun
The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, China
Search for more papers by this authorJ. Jia
The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, China
Search for more papers by this authorJ. Zhang
The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
Search for more papers by this authorCorresponding Author
Y.-F. Zhao
The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, China
Correspondence
Gang Chen and Yi-Fang Zhao.
E-mails:[email protected] and [email protected]
Search for more papers by this authorFunding sources:
This research was supported by the Doctoral Program Foundation of Higher Education of China to G.C. (20130141120089) and Y.-F.Z (20130141130006), and by grants from the National Natural Science Foundation of China to G.C. (81300895) and Y.-F.Z (81170977, 81371159).
Conflicts of interest:
None declared.
Summary
Background
Previous studies have implicated vascular destabilization and changes in extracellular matrix (ECM) composition in venous malformations (VMs).
Objectives
To evaluate the expression levels of the connective tissue growth factor (CCN) family of matricellular proteins in VMs and explore their association with vascular destabilization.
Methods
The expression levels of CCNs 1–6, transforming growth factor (TGF)-β, phosphorylated Tie2 and phosphorylated platelet-derived growth factor receptor β in normal human skin tissues and VMs were detected by immunohistochemistry. Correlation between tested proteins was explored using the Spearman rank correlation test, followed by clustering analysis. In vitro studies using human umbilical vein endothelial cells (HUVECs) were performed for mechanism investigation.
Results
Expression of CCN2 was found to be strongly positive in fibroblast-like cells, endothelial cells and around blood vessels in normal human skin tissues, but it was significantly downregulated in VMs. Correlation analyses showed that expression levels of CCN2 and TGF-β in VMs were positively correlated. The immunoreactivity of CCN2 was also closely correlated with perivascular α-smooth muscle cell actin+ cell coverage in VMs. Moreover, in vitro studies in HUVECs indicated that CCN2 might act as a downstream target of TGF-β, as demonstrated by the findings that treatment with exogenous TGF-β or exogenous CCN2 could significantly upregulate the expression level of CCN2, and increase the expression levels of ECM components. Upregulation of the TGF-β/CCN2 pathway was also detected in bleomycin-treated VM specimens.
Conclusions
This study unmasks the downregulation of the TGF-β/CCN2 pathway in VMs, and indicates its target potential for sclerotherapy.
Supporting Information
| Filename | Description |
|---|---|
| bjd12977-sup-0001-AppendixS1-FigS1.docWord document, 1.7 MB | Appendix S1. Supplementary materials and methods. Fig S1. The hierarchical clustering analyses of 23 venous malformations (VMs) and 6 normal human skin (SK) tissues. Transforming growth factor (TGF)-β and connective tissue growth factor (CCN)2 clustered most closely, followed by phosphorylated Tie2 (p-Tie2). However, CCN3 and phosphorylated platelet-derived growth factor receptor β (p-PDGFRβ) were distantly clustered. Moreover, all SK samples (cluster 1) and most of the VM samples (cluster 2) were clustered together, indicating significant differences. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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