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新生血管形成通过提供潜伏转化生长因子-β促进肝纤维化。

Neovessel formation promotes liver fibrosis via providing latent transforming growth factor-β.

机构信息

Micro-signaling Regulation Technology Unit, RIKEN Center for Life Science Technologies, Wako, Saitama 351-0198, Japan; Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Kanagawa 223-8522, Japan; Drug Discovery Laboratory, Wakunaga Pharmaceutical Co., Ltd., Akitakata, Hiroshima 739-1195, Japan.

Micro-signaling Regulation Technology Unit, RIKEN Center for Life Science Technologies, Wako, Saitama 351-0198, Japan.

出版信息

Biochem Biophys Res Commun. 2014 Jan 17;443(3):950-6. doi: 10.1016/j.bbrc.2013.12.074. Epub 2013 Dec 19.

Abstract

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)-β, the precursor of the most fibrogenic cytokine TGF-β.

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-β 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 α-smooth muscle actin (α-SMA) expression, hepatic contents of hydroxyproline, and latency associated protein degradation products, which reflects cell surface activation of TGF-β 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-β 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-β that activated on the surface of HSCs by PLK, thereby resultant active TGF-β stimulates the activation of HSCs.

摘要

目的

在肝脏疾病进展过程中,肝纤维化和血管生成并行发生。纤维化通过诱导激活的肝星状细胞(HSCs)中的血管内皮生长因子(VEGF)促进血管生成。反过来,增加的新血管形成导致纤维化,尽管潜在的分子机制仍未确定。在本研究中,我们旨在研究内皮细胞(ECs)作为潜在转化生长因子(TGF)-β的来源的作用,TGF-β是最纤维化细胞因子 TGF-β的前体。

方法

通过尾静脉向小鼠给予重组 VEGF 后,通过免疫组织化学和生化分析以及对原代培养的 HSCs 和肝窦内皮细胞(LSECs)中 TGF-β激活的研究,评估肝血管生成和纤维化。

结果

除了增加肝组织中 CD31 的表达外,VEGF 处理的小鼠还表现出α-平滑肌肌动蛋白(α-SMA)表达增加、肝羟脯氨酸含量增加和潜伏相关蛋白降解产物增加,这反映了通过血浆激肽(PLK)使 TGF-β在细胞表面激活。通过用其特异性磷脂酶 C 切割连接磷脂酰肌醇的束缚磷脂酶将 HSC 表面上的 PLK-尿激酶纤溶酶原激活物受体复合物释放出来,可抑制 LSEC 条件培养基中存在的激活潜伏 TGF-β,并随后抑制 HSC 激活。

结论

新血管形成(血管生成)至少部分通过 PLK 在 HSCs 表面激活的潜在 TGF-β加速肝纤维化,从而导致活性 TGF-β刺激 HSCs 的激活。

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