Endothelial nitric oxide signaling in cellular and systemic metabolism

Endothelial cell-derived nitric oxide (NO) is best known for its role in the regulation of vascular tone. However, growing evidence shows that endothelial NO acts as a flux- and compartment-dependent redox regulator of cellular and systemic metabolism. NO directly modulates metabolic networks through reversible or irreversible chemical modification of iron centers, reactive cysteine and tyrosine residues as well as fatty acids. Mechanisms of NO-mediated regulation of cellular metabolism include the S-nitrosation of enzymes involved in glycolysis, oxidative phosphorylation and nucleotide biosynthesis as well as the control of iron and heme availability. NO-derived nitrating species additionally generate electrophilic nitro-fatty acids, which act on metabolic and redox transcriptional programs through reversible cysteine adduction. Moreover, specialized endothelial cells contribute to metabolic regulation across organs, for example lipid trafficking in adipose tissue, iron homeostasis in the liver and erythropoiesis in the bone marrow. Finally, tissue/organ-specific endothelial dysfunction may disrupt organ and systemic metabolic control through multiple mechanisms, raising new questions and therapeutic opportunities. Understanding how cell- and enzymatic source-specific NO signaling defines endothelial heterogeneity and function may provide a mechanistic framework to address organ-specific endothelial dysfunction in cardiometabolic disease.