Progerin-Induced Impairment in Wound Healing and Proliferation in Vascular Endothelial Cells

Yizhi Jiang,Julie Y. Ji

doi:10.3389/fragi.2022.844885

Abstract

Progerin as a mutated isoform of lamin A protein was first known to induce premature atherosclerosis progression in patients with Hutchinson-Gilford progeria syndrome (HGPS), and its role in provoking an inflammatory response in vascular cells and accelerating cell senescence has been investigated recently. However, how progerin triggers endothelial dysfunction that often occurs at the early stage of atherosclerosis in a mechanical environment has not been studied intensively. Here, we generated a stable endothelial cell line that expressed progerin and examined its effects on endothelial wound repair under laminar flow. We found decreased wound healing rate in progerin-expressing ECs under higher shear stress compared with those under low shear. Furthermore, the decreased wound recovery could be due to reduced number of cells at late mitosis, suggesting potential interference by progerin with endothelial proliferation. These findings provided insights into how progerin affects endothelial mechanotransduction and may contribute to the disruption of endothelial integrity in HGPS vasculature, as we continue to examine the mechanistic effect of progerin in shear-induced endothelial functions.

Highlights

The global prevalence of cardiovascular diseases (CVD) has led to numerous studies investigating the associated lifestyle-related or genetic risk factors
Recent research has highlighted the importance of endothelial and vascular cell dysfunction in Hutchinson-Gilford progeria syndrome (HGPS) models, as well as progerin-induced mechano-sensitivity in the endothelium (Benedicto et al, 2021)
While progerin in endothelial cells has been shown to induce inflammatory responses and impaired mechanotransduction (Osmanagic-Myers et al, 2019). this is a more specific study on how progerin interferes with an endothelial wound recovery

Summary

Introduction

The global prevalence of cardiovascular diseases (CVD) has led to numerous studies investigating the associated lifestyle-related or genetic risk factors. Endothelial injury or denudation at the local area as well as a delayed or impaired reendothelialization process could result in the exposure of the internal membrane and vascular smooth muscle cells (VSMCs) to the circulating blood, creating a pro-thrombotic environment that provoked platelet adhesion and the aggregation of inflammatory cells (Shirali et al, 2016; Mastenbroek et al, 2020). The capacity of endothelial cells (ECs) to restore their integrity from injuries can be enhanced by applying normal shear stress (Xia et al, 2012). The correlations between local wall shear stress (WSS) and atherosclerosis revealed by in vivo observations and computational modeling studies (Heo et al, 2014; Park et al, 2016) indicate the beneficial roles of steady laminar flow in providing athero-protective effect via regulating EC proliferation and further remodeling process (Gimbrone and Garcia-Cardena, 2013; Roux et al, 2020). On the other hand, disturbed flow found at bifurcations and curvatures

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