Urolithin A and Endothelial Nitric Oxide Production
Yes, urolithin A increases nitric oxide production in the endothelium through activation of endothelial nitric oxide synthase (eNOS) and direct enhancement of NO bioavailability. 1
Direct Effects on Endothelial NO Production
The most compelling evidence comes from in vitro studies demonstrating that urolithin A directly stimulates NO release in human aortic endothelial cells:
- A mixture of urolithins at 5 μM significantly increased nitrite/nitrate levels after 24 hours of incubation in primary human aortic endothelial cells (HAECs). 1
- Urolithin B-glucuronide at 15 μM activated eNOS expression, the enzyme responsible for NO synthesis in endothelial cells. 1
- Urolithin A pretreatment mitigated endothelial inflammation by promoting NO production in TNF-α-stimulated human umbilical vein endothelial cells (HUVECs). 2
Mechanism of Action
The mechanism appears to involve both direct eNOS activation and reduction of factors that impair NO bioavailability:
- Urolithin A decreases YAP/TAZ protein expression and TEAD transcriptional activity, which promotes NO production in inflamed endothelial cells. 2
- The compound works independently of the NF-κB p65 pathway, suggesting a distinct anti-inflammatory mechanism that preserves endothelial NO production. 2
Clinical Relevance and Vascular Function
The NO-enhancing effects translate to measurable improvements in vascular function:
- Urolithin A intake improved flow-mediated vasodilatation (FMD) scores in participants with relatively poor baseline vascular endothelial function, particularly in those with low Bacillota/Bacteroidota ratios. 3
- The compound decreased endothelial adhesion molecule expression and reduced intraplaque hemorrhage in atherosclerotic models, consistent with improved endothelial NO bioavailability. 2
Important Caveats
The effectiveness of urolithin A depends critically on individual gut microbiota composition. 3 Participants who showed FMD improvement had specific baseline characteristics: poor initial FMD values and low Bacillota/Bacteroidota ratios. This means not all individuals will respond equally to urolithin A supplementation.
Dosing considerations matter: The mixture of urolithins at lower concentrations (5 μM each) was more effective than single urolithins at higher concentrations (15 μM) for increasing NO bioavailability. 1 This suggests synergistic effects between different urolithin metabolites.
The compound undergoes metabolic conjugation with sulfate moieties in cells, which may affect its bioactivity and duration of action. 1
Comparison to Established NO Modulators
For context, the endothelium normally produces NO through eNOS, which requires L-arginine as substrate and is regulated by shear stress, calcium signaling, and various post-translational modifications. 4 Urolithin A appears to enhance this system rather than replace it, making it complementary to established approaches like L-arginine supplementation that have shown benefits in conditions with impaired NO production. 4