Transcriptome characterization of venous endothelium during the formation of neointimal hyperplasia and stenosis in a rat arteriovenous fistula model for kidney dialysis

In patients with severe kidney disease AVF are surgically placed in order to create good access for hemodialysis. In these dialysis patients the failure rates of AVF can be as high as 24% within 6 months after surgery, causing ineffective dialysis and necessitating additional clinical interventions. The pathological processes known to lead to AVF failure are beginning to be unravelled include the formation of venous neointimal hyperplasia (VNIH), thrombosis (Chang et al. PMID 16105066), and venous stenosis (Kanterman et al. PMID7892454, Tang et al. 1998), resulting in a reduced blood flow through the fistula. We established a rat model for AVF failure in human kidney dialysis patients. The characterization of this model has been previously described (Globerman et al. 2011, PubmedID:22002501). In this model the AVFs are surgically constructed in the right leg by connecting the superficial epigastric vein SEV to the common femoral artery (CFA), resulting in exposure of the SEV to arterial pressure with pulsatile and low resistant flow patterns (Globerman et al. 2011, PMID22002501). In the present study we utilized this AVF model in order to assess the effects of arterialized flow, with consequent pathological changes of the vessel wall due to surgical AVF instalment, on the transcriptome of endothelium from the SEV. Within the SEV these pathologies of the vessel wall include the formation of NIH in the main branch, and stenosis in the side branches. By employing this rat model we assessed the changes of the endothelial transcriptome in relation to these pathologies in order to gain mechanistic understanding of the potential roles of venous endothelium in AVF failure, as well as to identify potential biomarkers preceding AVF failure.针对重症肾病患者，临床常通过外科手术置入动静脉内瘘（Arteriovenous Fistula, AVF）以建立良好的血液透析通路。此类透析患者的动静脉内瘘术后6个月内失败率可高达24%，会导致透析无效，且需要额外的临床干预手段。目前已知可导致动静脉内瘘失败的病理过程正逐步被阐明，包括静脉内膜增生（Venous Neointimal Hyperplasia, VNIH）、血栓形成（Chang等，PMID 16105066）以及静脉狭窄（Kanterman等，PMID 7892454；Tang等，1998），上述病理改变会使内瘘血流量降低。本研究团队构建了适用于人类肾病透析患者动静脉内瘘失败研究的大鼠模型，该模型的特征此前已被报道（Globerman等，2011，PubMed ID: 22002501）。该模型通过外科手术在大鼠右侧腿部将腹壁浅静脉（Superficial Epigastric Vein, SEV）与股总动脉（Common Femoral Artery, CFA）吻合以构建动静脉内瘘，使腹壁浅静脉暴露于动脉压力下，承受搏动性低阻力血流模式（Globerman等，2011，PMID 22002501）。本研究利用该动静脉内瘘模型，探究动脉化血流（因手术构建动静脉内瘘引发的血管壁病理性改变）对腹壁浅静脉内皮细胞转录组的影响。该模型中腹壁浅静脉的血管壁病理改变包括主干内膜增生以及分支静脉狭窄。本研究借助该大鼠模型，分析与上述病理改变相关的内皮细胞转录组变化，以期阐明静脉内皮细胞在动静脉内瘘失败过程中的潜在作用机制，并筛选出动静脉内瘘失败前的潜在生物标志物。