Rationale: Elevated shear stress induces vascular remodeling in veins exposed to arterial blood flow, which can lead to arterio-venous (AV) fistula failure. The molecular mechanisms driving remodeling have not been comprehensively examined with single cell resolution before.
Objective: Using an in vivo animal mode, single-cell RNA-sequencing (scRNA-seq), 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 elevated shear stress (ESS). Saphenous veins with no elevated shear stress (NSS) were anastomosed as controls.
Findings: ESS promoted transcriptional homogeneity, and NSS cells promoted considerable heterogeneity. Specifically, ESS ECs showed a more homogeneous transcriptional response promoting angiogenesis and upregulating Endothelial-to-Mesenchymal-Transition (EndMT) inhibiting genes (Klf2). NSS ECs upregulated anti-proliferation genes such as Cav1, Cst3 and Btg1. In macrophages, ESS promoted a large homogeneous subpopulation, creating a mechanically activated pro-inflammatory M1-like, thus pro-angiogenic myeloid phenotype, while NSS myeloid cells expressed the anti-inflammatory and anti-angiogenetic 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.