Mikirova Nina A, Casciari Joseph J, Riordan Neil H
Bio-Communications Research Institute, Wichita, Kansas, USA.
J Angiogenes Res. 2010 Jan 18;2:2. doi: 10.1186/2040-2384-2-2.
Angiogenesis is critical to tumor growth and is therefore a potential target for cancer therapy. As many current inhibitors of angiogenesis exhibit host toxicity, natural alternatives are needed. At millimolar concentrations, ascorbate (vitamin C) inhibits migration and tubule formation by mature endothelial cells and endothelial progenitors. In the present study, we examined the effects of ascorbate, at levels relevant during intravenous infusion therapy, on angiogenesis using an ex vivo an in vivo assay.
Two assays were used to evaluate effect of high-doses ascorbic acid on angiogenesis: ex vivo rat aortic ring explant assay in Matrigel matrices and in vivo Matrigel plug assay. In aortic rings, we quantified microvessel growth, branching and vessel regression under different treatment conditions. In murine angiogenesis assay, male C57 mice 6-8 weeks old were treated by high-dose ascorbic acid and the number of microvessels was analyzed by histological method. To characterize the population of cells that formed capillary network and microvessels, the sections were stained by CD34 and CD31 antibodies.
Results show that sprouting of endothelial tubules from aortic rings was reduced in a concentration-dependent fashion by ascorbate: while controls roughly tripled sprout densities during the study, ascorbate (1 mg/mL, 5.5 mM) actually reduced sprout density. In vivo, the ability of mice to vascularize subcutaneously implanted Matrigel plug was diminished if the mice were treated with 430 mg/kg vitamin C: numbers of vessels, and vessel densities, in plugs from treated mice were roughly 30% less than those in plugs from untreated mice.
We conclude that the inhibition of angiogenesis by ascorbate suggested in vitro is confirmed in vivo, and that angiogenesis inhibition may be one mechanism by which intravenous ascorbate therapy shows efficacy in animal experiments and clinical case studies.
血管生成对肿瘤生长至关重要，因此是癌症治疗的一个潜在靶点。由于目前许多血管生成抑制剂具有宿主毒性，需要天然的替代物。在毫摩尔浓度下，抗坏血酸（维生素C）可抑制成熟内皮细胞和内皮祖细胞的迁移和小管形成。在本研究中，我们使用体外和体内试验，研究了静脉输注治疗期间相关水平的抗坏血酸对血管生成的影响。
使用两种试验来评估高剂量抗坏血酸对血管生成的影响：在基质胶基质中进行的体外大鼠主动脉环外植体试验和体内基质胶栓试验。在主动脉环试验中，我们量化了不同治疗条件下微血管的生长、分支和血管消退情况。在小鼠血管生成试验中，对6-8周龄的雄性C57小鼠进行高剂量抗坏血酸治疗，并通过组织学方法分析微血管数量。为了表征形成毛细血管网络和微血管的细胞群体，切片用CD34和CD31抗体染色。
结果表明，抗坏血酸以浓度依赖性方式减少了主动脉环内皮小管的芽生：在研究期间，对照组的芽生密度大致增加了两倍，而抗坏血酸（1mg/mL，5.5mM）实际上降低了芽生密度。在体内，如果用430mg/kg维生素C治疗小鼠，皮下植入基质胶栓的血管化能力会减弱：治疗小鼠的栓子中的血管数量和血管密度比未治疗小鼠的栓子中的大约少30%。
我们得出结论，体外显示的抗坏血酸对血管生成的抑制作用在体内得到证实，血管生成抑制可能是静脉注射抗坏血酸治疗在动物实验和临床病例研究中显示疗效的一种机制。
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