Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis.
OBJECTIVE
Although angiogenesis is closely associated with liver fibrosis, the angiogenic factors involved in liver fibrosis are not well characterized. Angiopoietin 1 is an angiogenic cytokine indispensable for vascular development and remodeling. It functions as an agonist for the receptor tyrosine kinase with immunoglobulin G-like and endothelial growth factor-like domains 2 (Tie2) and counteracts apoptosis, promotes vascular sprouting or branching, and stabilizes vessels.


METHODS
Liver samples from patients with liver fibrosis were evaluated for mRNA expression of angiogenic cytokines. Liver fibrosis was induced in BALB/c mice by either carbon tetrachloride (CCl(4)) or bile duct ligation (BDL). Hepatic stellate cells (HSCs) were isolated from BALB/c mice. We used an adenovirus expressing the extracellular domain of Tie2 (AdsTie2) to block angiopoietin signaling in mice and evaluated its effect on liver fibrosis.


RESULTS
mRNA expression level of angiopoietin 1 was increased in human fibrotic livers and correlated with the expression level of CD31, an endothelial cell marker. During experimental models of murine liver fibrosis, angiopoietin 1 was expressed by activated HSCs. In primary cultures, activated HSCs express and secrete angiopoietin 1 more abundantly than quiescent HSCs, and the inflammatory cytokine tumor necrosis factor-alpha stimulates its expression in an nuclear factor-kappaB-dependent manner. AdsTie2 inhibits angiogenesis and liver fibrosis induced by either CCl(4) or BDL.


CONCLUSIONS
These results reveal an angiogenic role of HSCs mediated by angiopoietin 1, which contributes to development of liver fibrosis. Thus, angiogenesis and hepatic fibrosis are mutually stimulatory, such that fibrosis requires angiogenesis and angiogenesis requires angiopoietin 1 from activated HSCs.
Taura
Kojiro
K
Department of Medicine, School of Medicine, University of California, San Diego, California, USA.
De Minicis
Samuele
S
Seki
Ekihiro
E
Hatano
Etsuro
E
Iwaisako
Keiko
K
Osterreicher
Christoph H
CH
Kodama
Yuzo
Y
Miura
Kouichi
K
Ikai
Iwao
I
Uemoto
Shinji
S
Brenner
David A
DA
D042683:Angiopoietin-1 / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D042787:Receptor, TIE-2 / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D042683:Angiopoietin-1; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D042787:Receptor, TIE-2