The arterial microenvironment: the where and why of atherosclerosis

Abstract

The formation of atherosclerotic plaques in the large and medium sized arteries is classically driven by systemic factors, such as elevated cholesterol and blood pressure. However, work over the past several decades has established that atherosclerotic plaque development involves a complex coordination of both systemic and local cues that ultimately determine where plaques form and how plaques progress. Although current therapeutics for atherosclerotic cardiovascular disease primarily target the systemic risk factors, a large array of studies suggest that the local microenvironment, including arterial mechanics, matrix remodelling and lipid deposition, plays a vital role in regulating the local susceptibility to plaque development through the regulation of vascular cell function. Additionally, these microenvironmental stimuli are capable of tuning other aspects of the microenvironment through collective adaptation. In this review, we will discuss the components of the arterial microenvironment, how these components cross-talk to shape the local microenvironment, and the effect of microenvironmental stimuli on vascular cell function during atherosclerotic plaque formation.

Keywords: atherosclerosis; extracellular matrix; inflammation; microenvironment; shear stress.

Figure 1. Microenvironmental Influence on Atherosclerotic Plaque Formation

Changes in the microenvironmental stimuli as vessels progress from early atherogenesis to clinically relevant atherosclerotic plaques.

Figure 2. Vascular Matrix by Arterial Layer

A. Depiction of the arterial intima, media, and adventitia in a human coronary artery. Dashed lines represent the internal and external elastic lamina. B. Changes in the primary vascular matrix components in the different arterial layers.

Figure 3. Mechanics and Matrix in Endothelial Activation

A. Schematic for the prevalence of atherosclerotic plaque formation throughout the arterial tree. Plaque-prone areas are indicated in brown. B. Association of different flow patterns with a protected or atheroprone endothelial cell phenotype. C. Mechanisms of differential endothelial activation due to changes in flow patterns and subendothelial matrix composition.

Figure 4. Inflammation and SMC in Vascular Matrix Remodeling

Matrix composition regulates SMC proliferation and migration into the neointima, where SMCs play a dominant role in extracellular matrix (ECM) synthesis. Macrophages and other leukocytes in the neointima destabilize the plaque by inhibiting ECM synthesis, secreting proteases that degrade the matrix, and promoting SMC apoptosis.