Abstract

Background: Factor Xa (FXa) is a mediator initiating and accelerating atherosclerosis (AS). Both macrophage and vascular smooth muscle cells (VSMCs) participate in AS progression. This study was aimed to investigate the mechanisms underlying the effects of the FXa inhibitor rivaroxaban on AS.Methods: Rivaroxaban was administered to AS mice. Primary macrophages were exposed to FXa, treated with rivaroxaban, and transfected with siRNA silencing protease-activated receptor 2 (PAR2), hypoxia-inducible factor 1α (HIF1α), delta-like receptor 4 (Dll4), and Akt. Interaction between macrophages and VSMCs was assessed by co-culturing systems. Atherosclerotic lesions were evaluated by oil red O stain. Fluorescent staining was used to determine the cell phenotypes. Secretions of inflammatory cytokines and collagen were assessed by ELISA and Sircol assays. Western blotting was used to evaluate the protein expression and phosphorylation levels.Results: Rivaroxaban reduced lesion area, accumulation of M1 macrophages, and contractile-synthetic phenotypic conversion of VSMCs in atherosclerotic plaques. FXa exposure induced polarization of macrophages toward M1 and Dll4 high expression, which were inhibited by PAR2, Akt1, and HIF1α silencing. Rivaroxaban treatment inhibited PAR2/Akt/HIF1α signaling activation and Dll4 expression in FXa-exposed macrophages. By cell-to-cell contact, M1 macrophages induced Notch signaling activation in VSMCs which committed contractile-synthetic conversion. Rivaroxaban treatment and Dll4 silencing incapacitated macrophage in inducing phenotypic conversion of VSMCs upon cell-to-cell contact.Conclusion: Rivaroxaban suppresses AS by inhibiting FXa-induced PAR2/Akt/HIF1α signaling activation-mediated macrophage M1 polarization and high Dll4 expression. These macrophages facilitated VSMCs to perform contractile-synthetic phenotypic conversion upon macrophage-VSMCs cell-to-cell contact.

Highlights

  • Vascular smooth muscle cells (VSMCs) are the main cell components of the arterial wall, which are responsible for maintaining the structural and functional integrities of arterial vessels

  • Administration of rivaroxaban, significantly decreased plaque area, iNOS, and OPN expression, but increased MYH11 expression in AS lesions of the aortic root of ApoE−/− mice. These results suggested that rivaroxaban inhibited plaque progression, possibly by manipulating macrophage M1 polarization and phenotypic conversion of VSMCs

  • In our in vivo study, rivaroxaban treatment blocked both macrophage M1 polarization and contractilesynthetic phenotypic conversion of VSMCs in atherosclerotic plaques. These results suggested that rivaroxaban was capable of suppressing the phenotypic conversion of VSMCs by reducing macrophage Delta-like 4 (Dll4) expression during the process of Factor Xa (FXa)-induced M1 polarization

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Summary

Introduction

Vascular smooth muscle cells (VSMCs) are the main cell components of the arterial wall, which are responsible for maintaining the structural and functional integrities of arterial vessels. When challenged by harmful stimuli, VSMCs lose the contractile properties and get converted into synthetic phenotypes, which is critical in atherosclerotic plaque formation and progression [2]. Previous investigations have suggested that the activation of the Notch signaling pathway by its specific ligand Delta-like 4 (Dll4) facilitated VSMCs to accomplish contractile-synthetic phenotypic conversion [3, 4]. Macrophages are the dominant immune cell type participating in the formation, progression, and evolution of atherosclerotic plaques [5]. The classically activated macrophages, namely the M1 phenotype, are believed to contribute to the growth and vulnerability of atherosclerotic plaques due to their pro-inflammatory properties [6]. Factor Xa (FXa) is a mediator initiating and accelerating atherosclerosis (AS). Both macrophage and vascular smooth muscle cells (VSMCs) participate in AS progression.

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