Nitric oxide (eNOS)

Nitric oxide (NO) is a gas that acts as a signaling molecule. Your blood-vessel lining (endothelium) makes it with an enzyme called eNOS (NOS3), converting L-arginine and oxygen into NO and L-citrulline (with a cofactor, BH4). The NO diffuses into the vessel's muscle cells, switches on an enzyme (guanylyl cyclase), raises cyclic GMP, and triggers relaxation. That is the main mechanism of flow-driven vasodilation. eNOS-made NO does more, too: it blocks platelet clumping, calms white-cell stickiness, and supports new blood-vessel growth. With age, eNOS activity falls. The reasons: less activating phosphorylation (at Ser-1177), more inhibitory phosphorylation (at Thr-495), lower BH4, and 'uncoupling' that makes eNOS produce superoxide instead of NO. The protective SIRT1-eNOS feedback loop also weakens (Puca et al. 2012). There is a backup route, though: the nitrate-nitrite-NO pathway. Dietary inorganic nitrate (rich in leafy greens and beetroot) is turned into nitrite by mouth bacteria, then into NO under low-oxygen, acidic conditions, partly making up for the eNOS decline (Rocha 2021). In a randomized trial, 12 weeks of oral sodium nitrite (80 mg/day) improved flow-mediated dilation in older adults (mean age ~68; range 50 to 79). The benefit came from suppressing mitochondrial oxidative stress, not from boosting eNOS directly (Rossman et al. 2021). Still, the evidence is mostly mechanistic or from small trials; whether lasting NO restoration extends healthspan in larger studies is open.

Last reviewed: June 22, 2026

This definition is educational and is not medical advice, a diagnosis, or treatment. Talk to a doctor about any health decisions. Read our full medical disclaimer