Hepatic Stellate Cells Secrete Angiopoietin 1 That Induces Angiogenesis in Liver Fibrosis
Hepatic Stellate Cells Secrete Angiopoietin 1 That Induces Angiogenesis in Liver Fibrosis
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DOI：
10.1053/j.gastro.2008.07.065
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发表时间：
2008-11-01
期刊：
影响因子：
29.4
通讯作者：
Brenner, David A.
中科院分区：
文献类型：
--
作者：
Taura, Kojiro;De Minicis, Saimuele;Brenner, David A.
背景和目标：虽然血管生成与肝纤维化密切相关，但参与肝纤维化的血管生成因子尚未得到很好的表征。血管生成素I是血管发育和重塑所必需的血管生成细胞因子。它作为受体酪氨酸激酶的激动剂与免疫球蛋白G样和内皮生长因子样结构域2（Tie 2），并抵消细胞凋亡，促进血管发芽或分支，并稳定血管。方法：检测肝纤维化患者肝组织中血管生成细胞因子mRNA的表达。采用四氯化碳（CCl_4）或胆管结扎（BDL）诱导BALB/c小鼠肝纤维化。从BALB/c小鼠中分离肝星状细胞（HSC）。我们使用腺病毒表达Tie 2的胞外结构域（AdsTie 2）阻断小鼠血管生成素信号传导，并评估其对肝纤维化的影响。结果如下：血管生成素1的mRNA表达水平在人纤维化肝脏中增加，并且与内皮细胞标记物CD 31的表达水平相关。在小鼠肝纤维化的实验模型中，血管生成素1由活化的HSC表达。在原代培养中，活化的HSC比静止的HSC更丰富地表达和分泌血管生成素I，并且炎性细胞因子肿瘤坏死因子-α以核因子-κ B依赖的方式刺激其表达。AdsTie 2抑制CCl 4或BDL诱导的血管生成和肝纤维化。结论：这些结果揭示了血管生成素1介导的HSC的血管生成作用，这有助于肝纤维化的发展。因此，血管生成和肝纤维化是相互刺激的，例如纤维化需要血管生成，而血管生成需要来自激活的HSC的血管生成素1。
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.