Abstract：
Rationale: Elevated shear stress (ESS) induces vascular remodeling in veins exposed to arterial blood flow, which can lead to arteriovenous (AV) fistula failure. The molecular mechanisms driving remodeling have not been comprehensively examined with a single-cell resolution before. Objective: Using an in vivo animal mode, single-cell RNA sequencing, and histopathology, we precisely manipulate blood flow to comprehensively characterize all cell subpopulations important during vascular remodeling. Methods: AV loops were created in saphenous vessels of rats using a contralateral saphenous vein interposition graft to promote ESS. Saphenous veins with no elevated shear stress (NSS) were anastomosed as controls. Findings: ESS promoted transcriptional homogeneity, and NSS promoted considerable heterogeneity. Specifically, ESS endothelial cells (ECs) showed a more homogeneous transcriptional response promoting angiogenesis and upregulating endothelial-to-mesenchymal transition inhibiting genes (Klf2). NSS ECs upregulated antiproliferation genes such as Cav1, Cst3, and Btg1. In macrophages, ESS promoted a large homogeneous subpopulation, creating a mechanically activated, proinflammatory and thus proangiogenic myeloid phenotype, whereas NSS myeloid cells expressed the anti-inflammatory and antiangiogenetic marker Mrc1. Conclusion: ESS activates unified gene expression profiles to induce adaption of the vessel wall to hemodynamic alterations. Targeted depletion of the identified cellular subpopulations may lead to novel therapies to prevent excessive venous remodeling, intimal hyperplasia, and AV fistula failure.
摘要：
背景：剪切应力升高会导致暴露于动脉血流的静脉血管重塑，这可能导致动静脉（AV）瘘衰竭。以前尚未用单细胞分辨率全面检查驱动重塑的分子机制。
目的：使用体内动物模式，单细胞RNA测序（scRNA-seq），和组织病理学，我们精确地操纵血流来全面表征血管重塑过程中重要的所有细胞亚群.
方法：使用对侧隐静脉介入移植物在大鼠的隐血管中创建AV环，以促进升高的剪切应力（ESS）。将无剪切应力（NSS）升高的隐静脉吻合作为对照。
结果：ESS促进转录同质性，和NSS细胞促进了相当大的异质性。具体来说,ESSEC显示出更均一的转录反应，可促进血管生成和上调内皮到间充质转化（EndMT）抑制基因（Klf2）。NSSEC上调抗增殖基因如Cav1、Cst3和Btg1。在巨噬细胞中，ESS促进了一个大的同质亚群，产生机械激活的促炎M1样，因此，促血管生成的骨髓表型，而NSS骨髓细胞表达抗炎和抗血管生成标志物Mrc1。
结论：ESS激活统一的基因表达谱，诱导血管壁适应血液动力学改变。确定的细胞亚群的靶向消耗可能导致新疗法，以防止过度的静脉重塑。内膜增生,和房室瘘失败。
目的：使用体内动物模式，单细胞RNA测序（scRNA-seq），和组织病理学，我们精确地操纵血流来全面表征血管重塑过程中重要的所有细胞亚群.
方法：使用对侧隐静脉介入移植物在大鼠的隐血管中创建AV环，以促进升高的剪切应力（ESS）。将无剪切应力（NSS）升高的隐静脉吻合作为对照。
结果：ESS促进转录同质性，和NSS细胞促进了相当大的异质性。具体来说,ESSEC显示出更均一的转录反应，可促进血管生成和上调内皮到间充质转化（EndMT）抑制基因（Klf2）。NSSEC上调抗增殖基因如Cav1、Cst3和Btg1。在巨噬细胞中，ESS促进了一个大的同质亚群，产生机械激活的促炎M1样，因此，促血管生成的骨髓表型，而NSS骨髓细胞表达抗炎和抗血管生成标志物Mrc1。
结论：ESS激活统一的基因表达谱，诱导血管壁适应血液动力学改变。确定的细胞亚群的靶向消耗可能导致新疗法，以防止过度的静脉重塑。内膜增生,和房室瘘失败。
