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首页> 外文期刊>BMC Biotechnology >PHDs inhibitor DMOG promotes the vascularization process in the AV loop by HIF-1a up-regulation and the preliminary discussion on its kinetics in rat
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PHDs inhibitor DMOG promotes the vascularization process in the AV loop by HIF-1a up-regulation and the preliminary discussion on its kinetics in rat

机译：PHDs抑制剂DMOG通过HIF-1a上调促进其在AV回路中的血管形成过程，并对其动力学进行初步探讨

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Background The Arterovenous Loop (AV Loop) model is a vascularization model in tissue engineering research, which is capable of generating a three dimensional in vivo unit with cells as well as the supporting vessels within an isolation chmaber. In our previous studies the AV loop in the isolation chamber was discovered to undergo hypoxia, characterized by Hypoxia Inducible Factor (HIF) up-regulation. The vascularization followed the increase of HIF-α temporally, while it was spatially positively correlated with the HIF-α level, as well. This study aims to prove that HIF-1a up-regulation is the stimulus for vascularization in the AV loop model. Method The AV loop model in rats was created by interposing a femoral vein graft into the distal ends of the contralateral femoral artery and vein, and the loop was embeded in fibrin matrix and fixed in isolation chamber. PHD (prolyl hydroxylases) inhibitor DMOG (Dimethyloxallyl Glycine) was applied systemically in the rats in 40 mg/KG at day 0 and day 3 (DMOG-1), or in 15 mg/KG at day 8, day10 and day12 (DMOG-2). Two weeks later the specimens were explanted and underwent morphological and molecular evaluations. Results Compared to the control group, in the DMOG-2 group the HIF-1α positive rate was siginicantly raised as shown in immunohistochemistry staining, accompanied with a smaller cross section area and greater vessel density, and a HIF-1α accumulation in the kidney. The mRNA of HIF-1α and its angiogenic target gene all increased in different extends. Ki67 IHC demostrate more positive cells. There were no significant change in the DMOG-1 group. Conclusion By applying DMOG systemically, HIF-1α was up-regulated at the protein level and at the mRNA level, acompanied with angiogenic target gene up-regulateion, and the vascularization was promoted correspondingly. DMOG given at lower dosage constantly after one week tends to have better effect than the group given at larger dosage in the early stage in this model, and promotes cell proliferation, as evidenced by Ki67 IHC. Thus, this study proves that HIF-1a up-regulation is the stimulus for vascularization in the AV loop model and that the process of the vessel outgrowth can be controlled in the AV Loop model utilizing this mechanism.
机译：背景技术动静脉环（AV Loop）模型是组织工程研究中的血管化模型，能够在隔离通道内生成带有细胞以及支持血管的三维体内单元。在我们先前的研究中，隔离室中的AV回路被发现发生缺氧，其特征在于缺氧诱导因子（HIF）上调。血管化在时间上跟随着HIF-α的增加，而在空间上也与HIF-α的水平呈正相关。这项研究旨在证明HIF-1a的上调是AV回路模型中血管生成的刺激因素。方法通过将股静脉移植物插入对侧股动脉和静脉的远端，建立大鼠AV环模型，将环嵌入纤维蛋白基质中并固定在隔离室中。 PHD（脯氨酰羟化酶）抑制剂DMOG（二甲基草酸甘氨酸）在大鼠的第0天和第3天（DMOG-1）以40 mg / KG的剂量或在第8天，第10天和第12天以15 mg / KG的剂量系统应用在大鼠中2）。两周后，将标本移出并进行形态和分子评估。结果与对照组相比，在DMOG-2组中，免疫组织化学染色显示HIF-1α阳性率显着升高，同时具有较小的横截面积和较大的血管密度，并且HIF-1α在肾脏中蓄积。 HIF-1α的mRNA及其血管生成靶基因均在不同程度上增加。 Ki67 IHC分解出更多阳性细胞。 DMOG-1组无明显变化。结论通过全身应用DMOG，HIF-1α在蛋白水平和mRNA水平上调，并伴随血管生成靶基因的上调，从而促进了血管形成。 Ki67 IHC证明，在此模型的早期阶段，连续一周以较低剂量给予DMOG的效果往往要好于在早期以较大剂量给予DMOG的效果，并促进细胞增殖。因此，这项研究证明，HIF-1a的上调是在AV回路模型中促进血管形成的刺激因素，并且可以使用该机制在AV回路模型中控制血管生长的过程。

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