Dysfunctional Vascular Endothelium as a Driver of Atherosclerosis: Emerging Insights Into Pathogenesis and Treatment

Abstract

Atherosclerosis, the chronic accumulation of cholesterol-rich plaque within arteries, is associated with a broad spectrum of cardiovascular diseases including myocardial infarction, aortic aneurysm, peripheral vascular disease, and stroke. Atherosclerotic cardiovascular disease remains a leading cause of mortality in high-income countries and recent years have witnessed a notable increase in prevalence within low- and middle-income regions of the world. Considering this prominent and evolving global burden, there is a need to identify the cellular mechanisms that underlie the pathogenesis of atherosclerosis to discover novel therapeutic targets for preventing or mitigating its clinical sequelae. Despite decades of research, we still do not fully understand the complex cell-cell interactions that drive atherosclerosis, but new investigative approaches are rapidly shedding light on these essential mechanisms. The vascular endothelium resides at the interface of systemic circulation and the underlying vessel wall and plays an essential role in governing pathophysiological processes during atherogenesis. In this review, we present emerging evidence that implicates the activated endothelium as a driver of atherosclerosis by directing site-specificity of plaque formation and by promoting plaque development through intracellular processes, which regulate endothelial cell proliferation and turnover, metabolism, permeability, and plasticity. Moreover, we highlight novel mechanisms of intercellular communication by which endothelial cells modulate the activity of key vascular cell populations involved in atherogenesis, and discuss how endothelial cells contribute to resolution biology - a process that is dysregulated in advanced plaques. Finally, we describe important future directions for preclinical atherosclerosis research, including epigenetic and targeted therapies, to limit the progression of atherosclerosis in at-risk or affected patients.

Keywords: atherosclerosis; disturbed flow; endothelial dysfunction; endothelial-to-mesenchymal transition; extracellular vesicles; inflammation resolution; targeted therapy; vascular endothelium.

FIGURE 1

The vascular endothelium directs site-specificity for plaque development and governs plaque progression. Both atheroprotective and atherogenic mechanisms are operative in endothelial cells (ECs) exposed to disturbed flow. EC-derived extracellular vesicles (EVs) mediate atheroprotective and atherogenic intercellular communication among ECs and between ECs and other immune and non-immune cell populations. Endothelial-to-mesenchymal transition (EndMT) contributes to the atherosclerotic disease process but may also maintain plaque stability.* ANXA2, annexin A2; ARHGAP18, Rho GTPase activating protein 18; COMP, cartilage oligomeric matrix protein; DNMT1, DNA methyltransferase 1; ERK5, extracellular signal-regulated kinase 5; HMGB1/2, high mobility group box protein 1/2; ID1, inhibitor of DNA binding 1; IL-1β, interleukin 1 beta; oxLDL, oxidized low-density lipoprotein; PLXND1, plexin D1; PRKAA1, protein kinase AMP-activated catalytic subunit alpha 1; SIRT1, sirtuin 1; SMC, smooth muscle cell; TGF-β, transforming growth factor beta; YAP, yes-associated protein; ZBTB46, zinc finger and BTB domain-containing protein 46.

FIGURE 2

The vascular endothelium is an emerging therapeutic target for atherosclerotic cardiovascular disease. Epigenic interventions including enhancer of zeste homologue 2 (EZH2) antagonism and sirtuin 1 (SIRT1) agonism allow for broad targeting of endothelial cell (EC) dysfunction but may have undesirable effects in other cell types and tissues. Anti-inflammatory and anti-angiogenic nanotherapies have reduced off-target effects and increased efficacy per dose, but require rigorous protocols for assessing composition and purity, as well as the development of long-term stability in storage and safety and efficacy in humans with cardiovascular disease. EndMT, endothelial-to-mesenchymal transition; Icam1, intercellular adhesion molecule 1; Icam2, intercellular adhesion molecule 2; IL-1β, interleukin 1 beta; NO, nitric oxide; Sele, selectin E; Selp, selectin P; siRNA, small interfering RNA; TNF-α, tumor necrosis factor alpha; Vcam1, vascular cell adhesion molecule 1.