Neovessel formation promotes liver fibrosis via providing latent transforming growth factor-β
Neovessel formation promotes liver fibrosis via providing latent transforming growth factor-β
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DOI：
10.1016/j.bbrc.2013.12.074
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发表时间：
2014-01-17
影响因子：
3.1
通讯作者：
Kojima, Soichi
中科院分区：
文献类型：
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作者：
Sakata, Kotaro;Eda, Satoshi;Kojima, Soichi
目的：在肝脏疾病的发展过程中，肝纤维化和血管生成平行发生。纤维化通过诱导活化的肝星状细胞(HSCs)产生血管内皮生长因子(VEGF)来促进血管生成。反过来，新生血管的形成增加会导致纤维化，尽管潜在的分子机制尚不清楚。在本研究中，我们旨在探讨内皮细胞(ECs)作为潜在的转化生长因子(TGF)-β的来源所起的作用。转化生长因子是最具纤维化作用的细胞因子的前体。方法：经尾静脉给药后，用免疫组织化学和生化分析检测小鼠肝血管生成和纤维化形成，并观察原代培养的HSC和肝窦内皮细胞(LSECs)对转化生长因子-β的激活。结果：除了增加肝脏CD31的表达水平外，经血管内皮细胞处理的小鼠肝脏α-平滑肌肌动蛋白(α-SMA)表达增加，肝脏羟脯氨酸含量增加，相关蛋白降解产物潜伏期增加。反映细胞表面通过血浆激肽释放酶(PLK)激活转化生长因子-β(TGF-β)。通过将PLK-尿激酶型纤溶酶原激活剂受体复合体与其特异性磷脂酶C连接，从HSC表面释放出PLK-尿激酶型纤溶酶原激活剂受体复合体，从而抑制LSEC条件培养液中潜在的转化生长因子-β的激活，从而抑制HSC的激活。结论：新生血管的形成(血管生成)至少部分地通过提供潜伏在HSC表面的由PLK激活的转化生长因子-β来加速肝纤维化，从而产生活性的转化生长因子-β刺激HSC的激活。(C)2013 Elsevier Inc.保留所有权利。
Aim: Hepatic fibrosis and angiogenesis occur in parallel during the progression of liver disease. Fibrosis promotes angiogenesis via inducing vascular endothelial growth factor (VEGF) from the activated hepatic stellate cells (HSCs). In turn, increased neovessel formation causes fibrosis, although the underlying molecular mechanism remains undetermined. In the current study, we aimed to address a role of endothelial cells (ECs) as a source of latent transforming growth factor (TGF)-beta, the precursor of the most fibrogenic cytokine TGF-beta.Methods: After recombinant VEGF was administered to mice via the tail vein, hepatic angiogenesis and fibrogenesis were evaluated using immunohistochemical and biochemical analyses in addition to investigation of TGF-beta activation using primary cultured HSCs and liver sinusoidal ECs (LSECs).Results: In addition to increased hepatic levels of CD31 expression, VEGF-treated mice showed increased alpha-smooth muscle actin (alpha-SMA) expression, hepatic contents of hydroxyproline, and latency associated protein degradation products, which reflects cell surface activation of TGF-beta via plasma kallikrein (PLK). Liberating the PLK-urokinase plasminogen activator receptor complex from the HSC surface by cleaving a tethering phosphatidylinositol linker with its specific phospholipase C inhibited the activating latent TGF-beta present in LSEC conditioned medium and subsequent HSC activation.Conclusion: Neovessel formation (angiogenesis) accelerates liver fibrosis at least in part via provision of latent TGF-beta that activated on the surface of HSCs by PLK, thereby resultant active TGF-beta stimulates the activation of HSCs. (C) 2013 Elsevier Inc. All rights reserved.