Taura Kojiro, De Minicis Samuele, Seki Ekihiro, Hatano Etsuro, Iwaisako Keiko, Osterreicher Christoph H, Kodama Yuzo, Miura Kouichi, Ikai Iwao, Uemoto Shinji, Brenner David A
Department of Medicine, School of Medicine, University of California, San Diego, California, USA.
Gastroenterology. 2008 Nov;135(5):1729-38. doi: 10.1053/j.gastro.2008.07.065. Epub 2008 Aug 3.
BACKGROUND & AIMS: 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.
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.
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.
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.
尽管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完全明确。血管生成素1是一种血管生成细胞因子，对血管发育和重塑必不可少。它作为具有免疫球蛋白G样和内皮生长因子样结构域2（Tie2）的受体酪氨酸激酶的激动剂，可抵抗细胞凋亡、促进血管芽生或分支并稳定血管。
对肝纤维化患者的肝脏样本进行血管生成细胞因子mRNA表达评估。通过四氯化碳（CCl₄）或胆管结扎（BDL）诱导BALB/c小鼠发生肝纤维化。从BALB/c小鼠中分离肝星状细胞（HSCs）。我们使用表达Tie2细胞外结构域的腺病毒（AdsTie2）来阻断小鼠体内的血管生成素信号，并评估其对肝纤维化的影响。
血管生成素1在人类纤维化肝脏中的mRNA表达水平升高，且与内皮细胞标志物CD31的表达水平相关。在小鼠肝纤维化实验模型中，血管生成素1由活化的HSCs表达。在原代培养中，活化的HSCs比静止的HSCs更大量地表达和分泌血管生成素1，炎性细胞因子肿瘤坏死因子-α以核因子-κB依赖的方式刺激其表达。AdsTie2可抑制由CCl₄或BDL诱导的血管生成和肝纤维化。
这些结果揭示了由血管生成素1介导的HSCs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相互促进，即纤维化需要血管生成，而血管生成需要活化的HSCs产生的血管生成素1。
