Elevated Shear Stress Modulates Heterogenous Cellular Subpopulations to Induce Vascular Remodeling

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.

Impact Statement

Developing therapies to control vascular remodeling and angiogenesis is of critical relevance to patients undergoing vascular surgery, especially those who suffer from arteriovenous fistula failure or vessel occlusion. Clinically effective pharmacotherapies to address this are currently not available. Recent work has shown that cellular cross talk among proinflammatory heterogeneous mechanically activated subpopulations is extremely important in many disease states, but the effects in vascular remodeling remain incompletely understood. Improving our understanding of how elevated shear stress affects vascular remodeling in multiple different cell types will help develop targeted therapeutics to either alleviate or intensify vascular remodeling.