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.

Recent Advances Regarding the Molecular Mechanisms of Triterpenic Acids: A Review (Part I)

“…Atherosclerosis can be defined as a chronic inflammatory process, which results in cholesterol accumulation in plaques within the arterial vessels, gradually restricting blood flow; the pathophysiological process begins with endothelium dysfunctions mediated by intra- and intercellular events triggered by proatherogenic stimuli [ 101 ]. AA can act as protective agent for the endothelial barrier in human aortic cells by inhibiting the effects of tumor necrosis factor (TNF)-α, thus stabilizing F-actin and diphospho-MLC and preventing the structural rearrangement of vascular endothelial cadherin and β-catenin [ 102 ]; therefore, AA can be potentially used as preventive agent in early atherosclerosis.…”

Novel Biomarkers of Atherosclerotic Vascular Disease—Latest Insights in the Research Field

“…Atherosclerosis is a multifactorial process, in which genetic, environmental, and classical cardiovascular risk factors underlie complex pathophysiological processes that determine endothelial dysfunction and subsequent plaque formation in the vascular wall. Atherosclerosis is a chronic inflammatory disease with global economic and medical importance, with an increasing prevalence in the context of the continuing development of society [1,2]. Atherosclerosis is the basis of the cardiovascular continuum which includes a variety of cardiovascular diseases (CVDs) such as myocardial infarction (MI), aortic aneurysm, peripheral vascular disease, or stroke.…”

The Beneficial Role of Nrf2 in the Endothelial Dysfunction of Atherosclerosis

“…Atherosclerosis is a chronic disease process involving lipid accumulation [ 13 ]. It begins with endothelial cell dysfunction and is arbitrated by a cascade of intracellular and intercellular responses [ 14 ]. Endothelial cell dysfunction results in the infiltration of low-density lipoprotein (LDL) particles and their subsequent oxidation to oxidized LDL (oxLDL) [ 15 ].…”

“…Communication between endothelial cells and other vascular cell populations in this atherogenic environment stimulates the release of proinflammatory cues, increasing the native inflammatory response and promoting atheromatous plaque development [ 18 ]. Reduced collagen synthesis and increased degradation due to inflammation cause progressive thinning of the fibrous cap, resulting in plaque rupture, thrombosis, and vascular occlusion [ 14 ]. The disturbance of vascular endothelial structure and function is a key link in the occurrence and development of atherosclerotic vascular diseases [ 19 – 21 ].…”