Proangiogenic cytokines as hypoxia-dependent factors stimulating migration of human hepatic stellate cells
Proangiogenic cytokines as hypoxia-dependent factors stimulating migration of human hepatic stellate cells
复制标题
DOI：
10.2353/ajpath.2007.060887
复制
发表时间：
2007-06-01
影响因子：
6
通讯作者：
Parola, Maurizio
中科院分区：
文献类型：
--
作者：
Novo, Erica;Cannito, Stefania;Parola, Maurizio
病理性血管生成与慢性肝病的纤维化进展相关。实验数据表明，缺氧和血管内皮生长因子 (VEGF) 可能会刺激活化的肌成纤维细胞样大鼠肝星状细胞 (HSC/MF) 中 I 型胶原的增殖和合成。在这项研究中，我们研究了缺氧、重组 VEGF 或血管生成素 1 (Ang-1) 是否可能影响其他重要的促纤维化特征。在人 HSC/MF 中，其组成性表达 VEGF 受体-1 和 -2（VIEGFR-1、VEGFR-2）以及 Ang-1 受体 Tie-2，暴露于缺氧、VEGF 或 Ang-1 会导致 Ras/Erk 依赖性的趋化作用和趋化性刺激。缺氧条件下人 HSC/MF 的迁移涉及 VEGF-A、Ang-1 和相关受体的上调，并且主要依赖于 VEGFR-2 (Flk-1)。在肝硬化大鼠肝脏或丙型肝炎病毒相关肝硬化患者的标本中，HSC/MF 在活跃的纤维发生区域（即，在发育不完全纤维化隔膜的前缘或侧缘）表达促血管生成因子和相关受体。本文提供的数据表明，VEGF 和 Ang-1 可能通过充当能够募集肌成纤维细胞样细胞的缺氧诱导、自分泌和旁分泌因子来促进纤维形成。此外，HSC/MF 除了其已确定的促纤维化作用外，还可能有助于慢性肝伤口愈合过程中的新生血管生成。
Pathological angiogenesis is associated with the fibrogenic progression of chronic liver diseases. Experimental data suggest that hypoxia and vascular endothelial growth factor (VEGF) may stimulate proliferation and synthesis of type I collagen in activated, myofibroblast-like rat hepatic stellate cells (HSC/MFs). In this study, we investigated whether hypoxia, recombinant VEGF, or angiopoietin 1 (Ang-1) may affect other crucial profibrogenic features. in human HSC/MFs, which constitutively express VEGF receptor-1 and -2 (VIEGFR-1, VEGFR-2) and the Ang-1 receptor Tie-2, exposure to hypoxia, VEGF, or Ang-1 resulted in a Ras/Erk-dependent stimulation of chemokinesis and chemotaxis. Migration of human HSC/MFs under hypoxic conditions involved up-regulation of VEGF-A, Ang-1, and related receptors and was mainly dependent on VEGFR-2 (Flk-1). in specimens from either cirrhotic rat livers or from patients with hepatitis C virus-related cirrhosis, HSC/MFs expressed proangiogenic factors and related receptors in areas of active fibrogenesis (ie, at the leading or lateral edge of developing incomplete fibrotic septa). Data presented herein suggest that VEGF and Ang-1 may contribute to fibrogenesis by acting as hypoxia-inducible, autocrine, and paracrine factors able to recruit myofibroblast-fike cells. Moreover, HSC/MFs, in addition to their established profibrogenic role, may also contribute to neoangiogenesis during chronic hepatic wound healing.