Nitric oxide and endothelium-dependent hyperpolarization mediated by hydrogen peroxide in health and disease

The endothelium plays crucial roles in modulating vascular tone by synthesizing and releasing endothelium-derived relaxing factors (EDRFs), including vasodilator prostaglandins, nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) factors. Thus, endothelial dysfunction is the hallmark of atherosclerotic cardiovascular diseases. Importantly, the contribution of EDRFs to endothelium-dependent vasodilatation varies in a distinct vessel size-dependent manner; NO mainly mediates vasodilatation of relatively large, conduit vessels (eg epicardial coronary arteries), while EDH factors in small resistance vessels (eg coronary microvessels). Endothelium-derived hydrogen peroxide (H₂O₂) is a physiological signalling molecule serving as one of the major EDH factors especially in microcirculations and has gained increasing attention in view of its emerging relevance for cardiovascular diseases. In the clinical settings, therapeutic approaches targeting NO (eg NO donors) or non-specific elimination of reactive oxygen species (eg antioxidant supplements) are disappointingly ineffective for the treatment of various cardiovascular diseases, in which endothelial dysfunction and coronary microvascular dysfunction are substantially involved. These lines of evidence indicate the potential importance of the physiological balance between NO and H₂O₂/EDH factor. Further characterization and better understanding of endothelium-dependent vasodilatations are important to develop novel therapeutic strategies in cardiovascular medicine. In this MiniReview, we will briefly summarize the current knowledge on the emerging regulatory roles of endothelium-dependent vasodilatations in the cardiovascular system, with a special reference to the two major EDRFs, NO and H₂O₂/EDH factor, in health and disease.