Endothelial dysfunction: are we ready to heed the vasculature’s early-warning signal?

Endothelial dysfunction (ED) refers to a spectrum of pathophysiological changes in the vascular endothelium that ultimately results in a loss of vascular homeostasis. Traditional cardiovascular risk factors (e.g. diabetes mellitus, smoking, dyslipidaemia and hypertension) are all associated with the development of ED via sustained and harmful effects, mediated by circulating stimuli such as pro-inflammatory tumour necrosis factor-alpha (TNF-alpha), oxidised low-density lipoprotein (ox-LDL), asymmetrical dimethyl-arginine (ADMA), angiotensin II and hyperglycaemia. 1 The underlying cellular mechanisms of ED are directly or indirectly related to the development of oxidative stress (particularly increased superoxide anion production via NADPH-oxidase and xanthine oxidase), which reduces the bioavailability of the main endothelial-derived vasodilator, nitric oxide (NO) via the reaction of superoxide with NO (thereby scavenging NO) to form peroxynitrite (ONOO-), a highly reactive molecule. The latter has the ability to uncouple endothelial NO synthase (eNOS), which further reduces NO production and simultaneously increases superoxide anion generation. 2 As a result, vascular endothelial function becomes compromised, manifesting as a loss of endothelium-dependent vasorelaxation, increased thrombosis, the development of a generalised pro-inflammatory state (increased expression of vascular adhesion molecules) and increased vascular permeability. 3 Ultimately, ED can develop into atherosclerosis. 2 The importance of ED as a potential predictor of long-term development of atherosclerosis and cardiovascular event rate 2 is evident by the high number of research articles on this topic (PubMed search with keywords: endothelial + dysfunction revealed 51 600 hits and approximately 3 000–4000 articles per year on this topic since 2005). Herein, however, lies both the greatest potential and challenge of current research into ED, namely translating the wealth of data obtained with laboratory-based research into scientifically validated predictive, diagnostic and even therapeutic tools in the clinical setting. As Mudau et al. explain in their comprehensive review article on the cellular mechanisms and clinical applications of ED in the current issue of this journal, there is no doubt that ED serves as a crucial pathophysiological link between traditional cardiovascular risk factors and the eventual development of atherosclerosis and ischaemic heart disease (IHD). 4 Particularly helpful in this regard is the fact that ED is an early, reversible event. 5 This presents researchers and clinicians with a golden opportunity to not only predict the development of atherosclerosis, IHD and possibly other cardiovascular events, but also prevent the development of these conditions by therapeutically reversing early vascular dysfunction. As Mudau and co-workers report, there are several biomarkers that …