Resolution of liver fibrosis requires myeloid cell-driven sinusoidal angiogenesis
Resolution of liver fibrosis requires myeloid cell-driven sinusoidal angiogenesis
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DOI：
10.1002/hep.27635
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发表时间：
2015-06-01
期刊：
影响因子：
13.5
通讯作者：
Stockmann, Christian
中科院分区：
文献类型：
--
作者：
Kantari-Mimoun, Chahrazade;Castells, Magali;Stockmann, Christian
血管生成是肝纤维化的关键特征。尽管认为肝窦重塑有助于肝纤维化的发生，但肝窦血管生成对肝纤维化消退的影响仍不明确。骨髓细胞，特别是巨噬细胞，不断浸润纤维化肝脏，并能深刻地促进肝窦的重塑。我们观察到纤维化的发展与肝血管内皮生长因子（VEGF）表达的降低以及纤维化瘢痕的窦状隙稀疏有关。相反，纤维化的消退的特征在于肝VEGF水平的升高和纤维化组织的血管再生。骨髓细胞中VEGF的基因消融或VEGF受体2信号传导的药理学抑制可防止这种血管生成反应和肝纤维化的消退。我们观察到基质金属蛋白酶的表达增加，以及减少表达的金属蛋白酶的组织抑制剂局限于窦内皮细胞响应髓细胞VEGF。值得注意的是，在恢复后重新引入骨髓细胞来源的VEGF恢复了胶原溶解活性和纤维化的消退。结论：我们确定骨髓细胞来源的VEGF作为肝内皮细胞降解细胞外基质的关键调节因子，从而揭示了血管生成和纤维化解决之间的意外联系。（肝病学2015;61：2042-2055）
Angiogenesis is a key feature of liver fibrosis. Although sinusoidal remodeling is believed to contribute to fibrogenesis, the impact of sinusoidal angiogenesis on the resolution of liver fibrosis remains undefined. Myeloid cells, particularly macrophages, constantly infiltrate the fibrotic liver and can profoundly contribute to remodeling of liver sinusoids. We observe that the development of fibrosis is associated with decreased hepatic vascular endothelial growth factor (VEGF) expression as well as sinusoidal rarefication of the fibrotic scar. In contrast, the resolution of fibrosis is characterized by a rise in hepatic VEGF levels and revascularization of the fibrotic tissue. Genetic ablation of VEGF in myeloid cells or pharmacological inhibition of VEGF receptor 2 signaling prevents this angiogenic response and the resolution of liver fibrosis. We observe increased expression of matrix metalloproteases as well as decreased expression of tissue inhibitor of metalloproteases confined to sinusoidal endothelial cells in response to myeloid cell VEGF. Remarkably, reintroduction of myeloid cell-derived VEGF upon recovery restores collagenolytic acitivity and the resolution of fibrosis. Conclusion: We identify myeloid cell-derived VEGF as a critical regulator of extracellular matrix degradation by liver endothelial cells, thereby unmasking an unanticipated link between angiogenesis and the resolution of fibrosis. (Hepatology 2015;61:2042-2055)