Potential of dietary nitrate in angiogenesis

Abstract

Endothelial dysfunction with impaired bioavailability of nitric oxide (NO) is the hallmark in the development of cardiovascular disease. Endothelial dysfunction leads to atherosclerosis, characterized by chronic inflammation of the arterial wall and stepwise narrowing of the vessel lumen. Atherosclerosis causes deprivation of adequate tissue blood flow with compromised oxygen supply. To overcome this undersupply, remodeling of the vascular network is necessary to reconstitute and sustain tissue viability. This physiological response is often not sufficient and therapeutic angiogenesis remains an unmet medical need in critical limb ischemia or coronary artery disease. Feasible approaches to promote blood vessel formation are sparse. Administration of pro-angiogenic factors, gene therapy, or targeting of microRNAs has not yet entered the daily practice. Nitric oxide is an important mediator of angiogenesis that becomes limited under ischemic conditions and the maintenance of NO availability might constitute an attractive therapeutic target. Until recently it was unknown how the organism provides NO under ischemia. In recent years it could be demonstrated that NO can be formed independently of its enzymatic synthesis in the endothelium by reduction of inorganic nitrite under hypoxic conditions. Circulating nitrite derives from oxidation of NO or reduction of inorganic nitrate by commensal bacteria in the oral cavity. Intriguingly, nitrate is a common constituent of our everyday diet and particularly high concentrations are found in leafy green vegetables such as spinach, lettuce, or beetroot. Evidence suggests that dietary nitrate supplementation increases the regenerative capacity of ischemic tissue and that this effect may offer an attractive nutrition-based strategy to improve ischemia-induced revascularization. We here summarize and discuss the regenerative capacity of dietary nitrate on the vascular system.

Keywords: Dietary; Hind limb; Nitrate; Regeneration; Vasculature.

Figures

Figure 1

Non-enzymatic nitric oxide formation. One-electron reduction of nitrite (NO2-) to NO by ferrous heme proteins like hemoglobin in the blood or myoglobin in the heart can occur under conditions of low oxygen (O2); the nitrite-reductase activity of these proteins contributes to NOS independent NO formation. eNOS: Endothelial NO synthase; iNOS: Inducible NO synthase; nNOS: Neuronal NO synthase.