Huang Xin, Guan Jibin, Sheng Zitong, Wang Menghua, Xu Tianhua, Guo Guangying, Wan Pengzhi, Tian Binyao, Zhou Junlei, Huang Aoran, Hao Junfeng, Yao Li
Department of Nephrology, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China.
College of Pharmacy, University of Minnesota, Minneapolis 55455, MN, USA.
J Transl Int Med. 2021 Dec 31;9(4):307-317. doi: 10.2478/jtim-2021-0045. eCollection 2021 Dec 1.
Vascular stenosis and angiogenesis are the major causes of short expectancy of arteriovenous fistula (AVF). Increased expression of vascular endothelial growth factor-A (VEGF-A) has been suggested to play an important role in the pathophysiologic process. Anti-VEGF has been proved to be effective on anti-angiogenesis and applied in clinical practice, but its effect on anti-stenosis remains to be verified before it could be applied to prevent stenosis of AVF. This study was aimed to evaluate the effect of local anti-VEGF therapy to prevent the formation of stenosis in the outflow vein in AVF and its mechanism.
Bioinformatics of VEGF-A and its downstream-regulated molecules from the STRING PPI database were analyzed in this study. The biopsy samples from outflow veins of AVF in patients and C57BL/6 mouse models were analyzed to examine the mechanisms of pathologic vascular stenosis associated with VEGF pathways and their potential therapeutic targets.
We found that the reduction of VEGF-A could downregulate downstream molecules and subsequently reduce the intimal hyperplasia and abnormal vascular remodeling by analyzing the STRING PPI database. Venous wall thickening, intimal neointima formation, and apoptosis of vascular endothelial cells in the proliferative outflow vein of the AVF were significantly more obvious, and upregulation of expression of VEGF was observed in dysfunctional AVF in patients. In mouse models, the expression of VEGF, Ephrin receptor B4 (EphB4), matrix metalloproteinase (MMP)2, MMP9, tissue inhibitor of metalloproteinase (TIMP)1, TIMP2, and caspase 3 in the control-shRNA surgical group was significantly higher than in the sham group ( < 0.05), and all of these indicators were significantly lower in lentiviral transfection group and Avastin group than in control-shRNA surgical group ( < 0.05) on the 14th day after AVF operation.
VEGF expression is significantly increased in vascular endothelial cells in stenosed or occluded outflow veins of dysfunctional AVF. Local injection of Avastin into the adventitia of the proximal outflow vein in autologous AVF procedure has an excellent potential to prevent the subsequent local stenosis of the proximal outflow vein.
血管狭窄和血管生成是动静脉内瘘（AVF）使用寿命短的主要原因。血管内皮生长因子 - A（VEGF - A）表达增加被认为在病理生理过程中起重要作用。抗VEGF已被证明在抗血管生成方面有效并应用于临床实践，但在应用于预防AVF狭窄之前，其抗狭窄作用仍有待验证。本研究旨在评估局部抗VEGF治疗预防AVF流出静脉狭窄形成的效果及其机制。
本研究分析了来自STRING PPI数据库的VEGF - A及其下游调节分子的生物信息学。对患者AVF流出静脉的活检样本和C57BL/6小鼠模型进行分析，以研究与VEGF途径相关的病理性血管狭窄机制及其潜在治疗靶点。
通过分析STRING PPI数据库，我们发现VEGF - A的减少可下调下游分子，随后减少内膜增生和异常血管重塑。在功能失调的AVF患者的增生性流出静脉中，静脉壁增厚、内膜新生内膜形成和血管内皮细胞凋亡明显更显著，并且在功能失调的AVF中观察到VEGF表达上调。在小鼠模型中，对照shRNA手术组中VEGF、 Ephrin受体B4（EphB4）、基质金属蛋白酶（MMP）2、MMP9、金属蛋白酶组织抑制剂（TIMP）1、TIMP2和半胱天冬酶3的表达在AVF手术后第14天显著高于假手术组（<0.05），并且慢病毒转染组和阿瓦斯汀组中的所有这些指标均显著低于对照shRNA手术组（<0.05）。
在功能失调的AVF狭窄或闭塞的流出静脉中，血管内皮细胞中的VEGF表达显著增加。在自体AVF手术中，将阿瓦斯汀局部注射到近端流出静脉的外膜具有预防近端流出静脉随后局部狭窄的良好潜力。
