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Downregulation of the transforming growth factor‐β/connective tissue growth factor 2 signalling pathway in venous malformations: its target potential for sclerotherapy
Author(s) -
Ren J.G.,
Chen G.,
Zhu J.Y.,
Zhang W.,
Sun Y.F.,
Jia J.,
Zhang J.,
Zhao Y.F.
Publication year - 2014
Publication title -
british journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.304
H-Index - 179
eISSN - 1365-2133
pISSN - 0007-0963
DOI - 10.1111/bjd.12977
Subject(s) - downregulation and upregulation , transforming growth factor , growth factor , extracellular matrix , myofibroblast , connective tissue , vascular endothelial growth factor , umbilical vein , biology , pathology , microbiology and biotechnology , cancer research , medicine , receptor , in vitro , fibrosis , biochemistry , gene , vegf receptors
Summary Background Previous studies have implicated vascular destabilization and changes in extracellular matrix ( ECM ) composition in venous malformations ( VM s). Objectives To evaluate the expression levels of the connective tissue growth factor ( CCN ) family of matricellular proteins in VM s and explore their association with vascular destabilization. Methods The expression levels of CCN s 1–6, transforming growth factor ( TGF )‐β, phosphorylated T ie2 and phosphorylated platelet‐derived growth factor receptor β in normal human skin tissues and VM s were detected by immunohistochemistry. Correlation between tested proteins was explored using the S pearman rank correlation test, followed by clustering analysis. In vitro studies using human umbilical vein endothelial cells ( HUVEC s) were performed for mechanism investigation. Results Expression of CCN 2 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 VM s. Correlation analyses showed that expression levels of CCN 2 and TGF ‐β in VM s were positively correlated. The immunoreactivity of CCN 2 was also closely correlated with perivascular α‐smooth muscle cell actin + cell coverage in VM s. Moreover, in vitro studies in HUVEC s indicated that CCN 2 might act as a downstream target of TGF ‐β, as demonstrated by the findings that treatment with exogenous TGF ‐β or exogenous CCN 2 could significantly upregulate the expression level of CCN 2, and increase the expression levels of ECM components. Upregulation of the TGF ‐β/ CCN 2 pathway was also detected in bleomycin‐treated VM specimens. Conclusions This study unmasks the downregulation of the TGF ‐β/ CCN 2 pathway in VM s, and indicates its target potential for sclerotherapy.