J-G Ren1, G Chen, J-Y Zhu, W Zhang, Y-F Sun, J Jia, J Zhang, Y-F Zhao. 1. 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.
Abstract
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.
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.
Authors: Maliha Sadick; Walter A Wohlgemuth; Roland Huelse; Bettina Lange; Thomas Henzler; Stefan O Schoenberg; Haneen Sadick Journal: Eur J Radiol Open Date: 2017-05-14