Hepatic Stellate Cells Secrete Angiopoietin 1 That Induces Angiogenesis in Liver Fibrosis

被引：247

作者：

Taura, Kojiro ^{[1
,2
]}

De Minicis, Saimuele ^{[1
]}

Seki, Ekihiro ^{[1
]}

Hatano, Etsuro ^{[2
]}

Iwaisako, Keiko ^{[2
]}

Osterreicher, Christoph H. ^{[1
]}

Kodama, Yuzo ^{[1
]}

Miura, Kouichi ^{[1
]}

Ikai, Iwao ^{[2
]}

Uemoto, Shinji ^{[2
]}

Brenner, David A. ^{[1
]}

机构：

[1] Univ Calif San Diego, Sch Med, Dept Med, La Jolla, CA 92093 USA

[2] Kyoto Univ, Grad Sch Med, Dept Surg, Kyoto, Japan

来源：

GASTROENTEROLOGY | 2008年 / 135卷 / 05期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1053/j.gastro.2008.07.065

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Background & Aims: Although angiogenesis is closely associated with liver fibrosis, the angiogenic factors involved in liver fibrosis are not well characterized. Angiopoietin I 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 (CCl4) 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 I more abundantly than quiescent HSCs, and the inflammatory cytokine tumor necrosis factor-a stimulates its expression in an nuclear factor-kappa B-dependent manner. AdsTie2 inhibits angiogenesis and liver fibrosis induced by either CCl4 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.

引用

页码：1729 / 1738

页数：10

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