Role of Vascular Endothelial Growth Factor in the Pathophysiology of Nonalcoholic Steatohepatitis in Two Rodent Models
Role of Vascular Endothelial Growth Factor in the Pathophysiology of Nonalcoholic Steatohepatitis in Two Rodent Models
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DOI：
10.1002/hep.26219
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发表时间：
2013-05-01
期刊：
影响因子：
13.5
通讯作者：
Geerts, Anja
中科院分区：
文献类型：
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作者：
Coulon, Stephanie;Legry, Vanessa;Geerts, Anja
非酒精性脂肪性肝炎（NASH）的病理生理学应作为一个多因素的过程。在NASH的几个阶段中，可以在疾病进展和肝脏微血管变化之间建立联系。在这项研究中，我们研究了血管生成在两种NASH小鼠模型中的作用，以及预防性和治疗性抗血管生成治疗在饮食诱导的NASH小鼠模型中的作用。在不同时间点，C56 BL/6和db/db NASH小鼠肝脏中血管生成因子和炎症因子的蛋白和RNA水平显著上调。为了检查血管生成因子对NASH疾病进展的影响，建立了阻断胎盘生长因子（PlGF）或血管内皮生长因子受体2（VEGFR 2）的预防和治疗研究。我们的研究表明，在预防和治疗背景下，治疗通过减轻脂肪变性和炎症来预防NASH的进展，从而证实了血管生成因子在从脂肪变性到NASH的疾病进展中起早期作用的假设。抗PlGF（α PlGF）没有显著改善肝组织学。血管腐蚀铸型显示，与对照组相比，NASH小鼠的肝脏血管系统受到更多破坏。用aVEGFR 2治疗显示肝血管系统的改善。此外，用aVEGFR 2处理的富含脂肪的原代肝细胞储存显著更少的脂质。结论：我们的研究结果表明，在不同的NASH小鼠模型中，肝脏中血管生成因子的表达增加。我们发现，在预防和治疗环境中，VEGFR 2阻断可减弱饮食诱导的NASH小鼠模型中的脂肪变性和炎症。我们的研究结果保证了进一步研究血管生成在NASH病理生理学中的作用。（肝脏学2013;57：1793-1805）
The pathophysiology of nonalcoholic steatohepatitis (NASH) should be approached as a multifactorial process. In several stages of NASH, a link between disease progression and hepatic microvasculature changes can be made. In this study we investigated the role of angiogenesis in two mouse models for NASH, and the effect of a preventive and therapeutic antiangiogenic treatment in a diet-induced mouse model for NASH. Protein and RNA levels of angiogenic and inflammatory factors were significantly up-regulated in the liver of C56BL/6 and db/db mice with NASH at different timepoints. To examine the effect of angiogenic factors on the disease progression of NASH, a prevention and treatment study was set up, blocking the placental growth factor (PlGF) or vascular endothelial growth factor receptor 2 (VEGFR2). Our study showed that treatment prevents the progression of NASH by attenuating steatosis and inflammation, both in a preventive and therapeutic setting, thereby confirming the hypothesis that angiogenic factors play an early role in the disease progression from steatosis to NASH. Anti-PlGF (alpha PlGF) did not significantly improve liver histology. Vascular corrosion casting showed a more disrupted liver vasculature in mice with NASH compared to controls. Treatment with alpha VEGFR2 showed an improvement of the liver vasculature. Moreover, fat-laden primary hepatocytes treated with aVEGFR2 stored significantly less lipids. Conclusion: Our results demonstrate that there is an increased expression of angiogenic factors in the liver in different mouse models for NASH. We found that VEGFR2 blockage attenuates steatosis and inflammation in a diet-induced mouse model for NASH in a preventive and therapeutic setting. Our findings warrant further investigation of the role of angiogenesis in the pathophysiology in NASH. (HEPATOLOGY 2013;57:1793-1805)