Targeting the ailing endothelium – current concepts and future prospects

Endothelial dysfunction is an independent predictor of cardiovascular risk and is present in many diseases. It is characterized by altered endotheliummediated vasodilation, increased vascular reactivity, platelet secretion and aggregation, thrombus formation, increased permeability, leukocyte adhesion and monocyte migration. Molecular mechanisms contributing to these processes include increased expression of adhesion molecules, increased synthesis of proinflammatory and prothrombotic factors, increased endothelin-1 secretion and enhanced oxidative stress. Decreased nitric oxide (NO) bioavailability, due to reduced NO synthesis by endothelial NO synthase and increased NO consumption by reactive oxygen species, underlies many of the molecular changes associated with impaired endothelial function. Vasoactive agents, including angiotensin II and endothelin-1; hyperglycemia; increased asymmetric dimethylarginine, an endogenous NOS inhibitor; and hyperhomocysteinemia contribute to these processes. Techniques for assessing endothelial dysfunction include ultrasonographic measurement of flow-mediated vasodilation of peripheral arteries and plethysmographic measurement of forearm blood flow responses to vasoactive agents. Measurement of circulating levels of endothelial-derived proinflammatory and prothrombotic mediators are increasingly being used as surrogate markers of endothelial function. Preventing endothelial damage by applying nonpharmacological and pharmacological strategies may protect against cardiovascular disease and improve endothelial function in patients with vascular injury. The present review discusses the importance of the endothelium in health and disease, and focuses on strategies to prevent and treat endothelial dysfunction. In particular, novel NO-based therapies and the therapeutic potential of circulating endothelial progenitor cells are highlighted