In Development—A New Paradigm for Understanding Vascular Disease

Abstract

Under physiological conditions, the arterial endothelium exerts a powerful protective influence to maintain vascular homeostasis. However, during the development of vascular disease, these protective activities are lost and dysfunctional endothelial cells actually promote disease pathogenesis. Numerous investigations have analyzed the characteristics of dysfunctional endothelium with a view to understanding the processes responsible for the dysfunction and to determining their role in vascular pathology. The present review adopts an alternate approach: reviewing the mechanisms that contribute to the initial formation of a healthy protective endothelium and on how those mechanisms may be disrupted, precipitating the appearance of dysfunctional endothelial cells and the progression of vascular disease. This approach, which highlights the role of endothelial adherens junctions and VE-cadherin in endothelial maturation and endothelial dysfunction, provides new insight into the remarkable biology of this important cell layer and its role in vascular protection and vascular disease.

Impaired activity of adherens junctions contributes to endothelial dilator dysfunction in ageing rat arteries

“…; Giannotta et al . ; Flavahan, ). Internalization and degradation of VE‐cadherin would not only reduce the protective activity of endothelial adherens junctions, but would also release β‐catenin (Valenta et al .…”

“…). Impaired activity of endothelial adherens junctions also plays a key role in the initiation and progression of the atherosclerotic process, contributing to a breakdown in the endothelial barrier and enabling the subendothelial accumulation of atherogenic lipids, increased inflammatory activity and increased monocyte transmigration, and contributing to formation and expansion of the atherosclerotic plaque (Flavahan, ). Therefore, an ageing‐induced impairment of endothelial adherens junctions would be expected to amplify these pathological processes and contribute importantly to ageing‐induced deterioration of cardiovascular and organ function.…”

“…; Flavahan et al . ; Flavahan, ). Protective features of arterial endothelial cells become fully engaged during the early postnatal period (Flavahan et al .…”

“…; Giannotta et al . ; Flavahan, ). The present experiments were performed to determine whether ageing impairs the activity of endothelial adherens junctions and whether this could contribute to the ageing‐induced dysfunction in endothelial dilatation.…”

Superoxide inhibition restores endothelium-dependent dilatation in aging arteries by enhancing impaired adherens junctions

“…Aging disrupts the normal protective activity of arterial endothelial cells, including nitric oxide (NO)-mediated endothelium-dependent dilatation (4,6,8). This aging-induced endothelial dysfunction contributes to structural and functional deterioration of the arterial system and to the amplification of cardiovascular diseases (8).…”