Immature Vascular Smooth Muscle Cells in Healthy Murine Arteries and Atherosclerotic Plaques: Localization and Activity.

Alexander Balatskiy,Maria Balatskaya,Vladimir Popov,Julia Filatova,Natalia Kalinina,Alexandra Savina,Vsevolod Tkachuk,Ilia Ozhimalov

doi:10.3390/ijms23031744

Abstract

The local development of atherosclerotic lesions may, at least partly, be associated with the specific cellular composition of atherosclerosis-prone regions. Previously, it was demonstrated that a small population of immature vascular smooth muscle cells (VSMCs) expressing both CD146 and neuron-glial antigen 2 is postnatally sustained in atherosclerosis-prone sites. We supposed that these cells may be involved in atherogenesis and can continuously respond to angiotensin II, which is an atherogenic factor. Using immunohistochemistry, flow cytometry, wound migration assay xCELLigence system, and calcium imaging, we studied the functional activities of immature VSMCs in vitro and in vivo. According to our data, these cells do not express nestin, CD105, and the leptin receptor. They are localized in atherosclerosis-prone regions, and their number increases with age, from 5.7% to 23%. Immature VSMCs do not migrate to low shear stress areas and atherosclerotic lesions. They also do not have any unique response to angiotensin II. Thus, despite the localization of immature VSMCs and the presence of the link between their number and age, our study did not support the hypothesis that immature VSMCs are directly involved in the formation of atherosclerotic lesions. Additional lineage tracing studies can clarify the fate of these cells during atherogenesis.

Highlights

Current concepts of atherogenesis suppose that atherosclerotic plaques occur in specific sites mainly due to the shear stress, which changes when the laminar blood flow turns into turbulent curvatures and bifurcations of the arteries
Platelet-derived growth factor receptor beta (CD140b) is a common marker for pericytes and vascular smooth muscle cells (VSMCs) [14], and it is abundant in the aortic wall, while leptin receptor was only be found in perivascular fat (Figure 1a)
In sorted neuron-glial antigen 2 (NG2)+CD146+ immature VSMCs, we find either cells responding to both adds of angiotensin II or only to the second add (Figure 12a)

Summary

Introduction

Current concepts of atherogenesis suppose that atherosclerotic plaques occur in specific sites mainly due to the shear stress, which changes when the laminar blood flow turns into turbulent curvatures and bifurcations of the arteries. It was demonstrated that a population of myointimal cells (myofibroblast-like) originates from the pericytes during arterial intimal thickening formation [7]. In 2018, Roostalu et al described a population considered as immature vascular smooth muscle cells (VSMCs) expressing pericytic markers CD146 and neuron-glial antigen 2 (NG2). Roostalu et al showed that these cells express yes-associated protein 1 (YAP1), which is one of the key participants in the mechanoreception signaling cascades. This suggests the sensitivity of NG2+CD146+ cells to shear stress. The authors believe that these cells are immature smooth muscle cells and not pericytes, as they respond to phenylephrine [8]

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