NAD⁺ and Vascular Dysfunction: From Mechanisms to Therapeutic Opportunities

Nicotinamide adenine dinucleotide (NAD⁺) is an essential and pleiotropic coenzyme involved not only in cellular energy metabolism, but also in cell signaling, epigenetic regulation, and post-translational protein modifications. Vascular disease risk factors are associated with aberrant NAD⁺ metabolism. Conversely, the therapeutic increase of NAD⁺ levels through the administration of NAD⁺ precursors or inhibitors of NAD⁺-consuming enzymes reduces chronic low-grade inflammation, reactivates autophagy and mitochondrial biogenesis, and enhances oxidative metabolism in vascular cells of humans and rodents with vascular pathologies. As such, NAD⁺ has emerged as a potential target for combatting age-related cardiovascular and cerebrovascular disorders. This review discusses NAD⁺-regulated mechanisms critical for vascular health and summarizes new advances in NAD⁺ research directly related to vascular aging and disease, including hypertension, atherosclerosis, coronary artery disease, and aortic aneurysms. Finally, we enumerate challenges and opportunities for NAD⁺ repletion therapy while anticipating the future of this exciting research field, which will have a major impact on vascular medicine.