Endothelial dysfunction in conduit arteries and in microcirculation. Novel therapeutic approaches

Abstract

The vascular endothelium not only is a single monolayer of cells between the vessel lumen and the intimal wall, but also plays an important role by controlling vascular function and structure mainly via the production of nitric oxide (NO). The so called “cardiovascular risk factors” are associated with endothelial dysfunction, that reduces NO bioavailability, increases oxidative stress, and promotes inflammation contributing therefore to the development of atherosclerosis. The significant role of endothelial dysfunction in the development of atherosclerosis emphasizes the need for efficient therapeutic interventions.

During the last years statins, angiotensin-converting enzyme inhibitors, angiotensin-receptor antagonists, antioxidants, beta-blockers and insulin sensitizers have been evaluated for their ability to restore endothelial function (Briasoulis et al., 2012). As there is not a straightforward relationship between therapeutic interventions and improvement of endothelial function but rather a complicated interrelationship between multiple cellular and sub-cellular targets, research has been focused on the understanding of the underlying mechanisms. Moreover, the development of novel diagnostic invasive and non-invasive methods has allowed the early detection of endothelial dysfunction expanding the role of therapeutic interventions and our knowledge.

In the current review we present the available data concerning the contribution of endothelial dysfunction to atherogenesis and review the methods that assess endothelial function with a view to understand the multiple targets of therapeutic interventions. Finally we focus on the classic and novel therapeutic approaches aiming to improve endothelial dysfunction and the underlying mechanisms.

Introduction

The vascular endothelium is a monolayer of cells between the vessel lumen and the vascular smooth muscle cells. It plays a pivotal role in the regulation of vascular function and structure by releasing various biochemical mediators, such as nitric oxide (NO) and prostacyclin (Tousoulis et al., 2012). A growing list of factors, including the so called “cardiovascular risk factors”, such as hypertension, hypercholesterolemia, smoking, diabetes mellitus, congestive heart failure, hyperhomocysteinemia and aging process itself, are associated with impaired endothelial function (Siasos et al., 2012). Endothelial dysfunction (ED), observed in these conditions, is characterized by decreased NO bioavailability and increased oxidative stress. As a result, ED promotes inflammation, oxidation of lipoproteins, platelet aggregation and thrombus formation and thus contributes to the development of atherosclerosis (Fig. 1).

Over the last years vascular endothelium has emerged as a new therapeutic target in cardiovascular disease. Several therapeutic approaches are currently available, targeting both synthesis and production of NO in human vascular endothelium, such as statins, angiotensin converting enzyme inhibitors, and thiazolidinediones and others are still under investigation (Table 1). Nevertheless, the impact of treatments in endothelial function is not constant while the underlying mechanisms are sometimes unknown. Moreover, there is a discrepancy between the achieved endothelial improvement and clinical outcome, thus further complicating the evaluation of treatment effects.

In the current review we present the available data concerning the contribution of endothelial dysfunction to atherogenesis and review the methods that assess endothelial function with a view to understand the multiple targets of therapeutic interventions. Finally we focus on the classic and novel therapeutic approaches aiming to improve endothelial dysfunction and the underlying mechanisms.