Endothelial to mesenchymal transition via transforming growth factor-beta1/Smad activation is associated with portal venous stenosis in idiopathic portal hypertension.

Abstract

Idiopathic portal hypertension (IPH) represents noncirrhotic portal hypertension of unknown etiology, mainly due to stenosis of peripheral portal veins. This study was performed to clarify the mechanism of portal venous stenosis in IPH from the viewpoint of the contribution of the endothelial to mesenchymal transition of the portal vein endothelium via transforming growth factor-beta1 (TGF-beta1)/Smad activation. In vitro experiments using human dermal microvascular endothelial cells demonstrated that TGF-beta1 induced myofibroblastic features in human dermal microvascular endothelial cells, including spindle cell morphology, reduction of CD34 expression, and induction of S100A4, alpha-smooth muscle actin, and COL1A1 expression, as well as the increased nuclear expression of phospho-Smad2. Bone morphogenic protein-7 preserved the endothelial phenotype of human dermal microvascular endothelial cells. Immunohistochemical analysis showed that endothelial cells of the peripheral portal veins in IPH were characterized by the decreased expression of CD34 and the enhanced nuclear expression of phospho-Smad2; these results also confirmed the expression of S100A4 and COL1A1 in the portal vein endothelium. Serum TGF-beta1 levels in patients with IPH were significantly higher than those of healthy volunteers and patients with chronic viral hepatitis/liver cirrhosis, while an elevation of serum bone morphogenic protein-7 levels was not observed. These results suggest that the endothelial to mesenchymal transition of the portal venous endothelium via TGF-beta1/Smad activation is associated with portal venous stenosis in IPH, and bone morphogenic protein-7 may therefore be a suitable therapeutic candidate for IPH.

• Authors: Azusa Kitao, Yasunori Sato, Seiko Sawada-Kitamura, Kenichi Harada, Motoko Sasaki, Hiroyasu Morikawa, Susumu Shiomi, Masao Honda, Osamu Matsui, Yasuni Nakanuma
• Journal: The American journal of pathology (Am J Pathol) Vol. 175 Issue 2 Pg. 616-26 (Aug 2009) ISSN: 1525-2191 [Electronic] United States
• PMID: 19608867 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD34
• BMP7 protein, human
• Bone Morphogenetic Protein 7
• SMAD2 protein, human
• Smad2 Protein
• Transforming Growth Factor beta1

Topics

• Antigens, CD34 (biosynthesis)
• Bone Morphogenetic Protein 7
• Endothelium (metabolism, pathology)
• Humans
• Hypertension, Portal (metabolism, pathology)
• Liver (metabolism, pathology)
• Mesoderm (metabolism, pathology)
• Portal Vein (metabolism, pathology)
• Smad2 Protein (biosynthesis)
• Transforming Growth Factor beta1 (biosynthesis)