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Nitric Oxide, NOS3, and What Your Genotype Means for Vascular and Metabolic Health

The NOS3 gene encodes endothelial nitric oxide synthase (eNOS), the enzyme that makes nitric oxide (NO) from the amino acid L-arginine. Nitric oxide is a small but vital signaling molecule that helps blood vessels relax, supports healthy blood flow, contributes to neurotransmission, and helps with ammonia detoxification through the urea cycle. eNOS requires the cofactor BH4 (tetrahydrobiopterin), which is connected to folate and methylation pathways. When BH4 is low or eNOS function is altered, the enzyme can produce damaging free radicals instead of NO, increasing inflammation and endothelial dysfunction.

How NOS3 Interacts with Other Pathways

  • BH4 is produced from metabolites tied to the folate and methionine cycles. Adequate 5-MTHF and SAMe support BH4 levels and optimal eNOS function.
  • Reduced NO can impair blood flow, increase oxidative stress, and strain the urea cycle, potentially affecting ammonia clearance and methylation efficiency.
  • Oxidative stress, nutrient deficiencies, and inflammation can lower BH4 and worsen eNOS uncoupling, creating a cycle that reduces NO and increases free radical production.

Practical Goals to Support NOS3 and Nitric Oxide Balance

  • Support BH4 and methylation: ensure adequate folate status and nutrients that support methylation cycles.
  • Provide NO substrates: arginine and citrulline can help supply the building blocks for NO synthesis.
  • Reduce oxidative stress: antioxidants and lifestyle measures preserve BH4 and prevent eNOS uncoupling.
  • Encourage vascular health: exercise and blood pressure management support healthy eNOS activity.

Diet Recommendations

  • Focus on folate-rich foods: leafy greens, legumes, asparagus, and beets to support 5-MTHF production.
  • Include natural sources of nitrate and nitrite: beets, spinach, arugula, and celery can boost NO through alternate pathways.
  • Eat arginine- and citrulline-containing foods: nuts, seeds, poultry, dairy, watermelon, and legumes.
  • Choose antioxidant-rich foods: colorful fruits and vegetables, nuts, seeds, and fatty fish to reduce oxidative stress.
  • Limit processed foods, excess alcohol, and high sugar intake which can increase inflammation and oxidative damage.

Supplement Suggestions (to discuss with your healthcare provider)

  • Active folate (5-MTHF) if dietary folate is insufficient or if methylation issues are suspected.
  • BH4 precursors and cofactors: where appropriate and supervised, supporting nutrients such as folate, vitamin B2 (riboflavin), and vitamin B6.
  • Antioxidants: vitamin C and vitamin E can protect BH4 and eNOS from oxidative damage.
  • L-citrulline or L-arginine supplements to support NO production, especially around exercise.
  • Omega-3 fatty acids for endothelial support and to reduce inflammation.

Lifestyle Recommendations

  • Regular aerobic and resistance exercise: increases eNOS expression and NO bioavailability.
  • Maintain healthy weight and body composition to reduce vascular inflammation.
  • Smoking cessation and limiting environmental exposures that increase oxidative stress.
  • Stress management and good sleep to reduce systemic inflammation.
  • Monitor blood pressure and metabolic health; maintain cardiovascular risk factors in healthy ranges.

Blood Tests and Monitoring

  • Basic metabolic panel and lipid profile to track cardiovascular risk.
  • High sensitivity C-reactive protein (hs-CRP) for systemic inflammation.
  • Folate and B12 levels to assess methylation support.
  • Homocysteine as an indirect marker of methylation efficiency.
  • Vitamin D and antioxidant status if clinically indicated.

Genetic Interpretation for rs1799983 (NOS3)

2 effect alleles — TT genotype

If your genotype is TT, you carry two copies of the effect allele associated with reduced NOS3 (eNOS) activity. This may lower nitric oxide production, which can affect blood vessel dilation, circulation, immune regulation, and ammonia detoxification via the urea cycle. Reduced NO and increased oxidative stress may also burden methylation pathways indirectly.

Consider prioritizing the following to support NO and BH4:

  • Ensure consistent intake of folate (preferably active 5-MTHF) and B vitamins to support BH4 synthesis and methylation.
  • Use antioxidants such as vitamin C and vitamin E to protect BH4 and limit eNOS uncoupling.
  • Supplementation with L-citrulline or L-arginine may help increase NO precursors, especially with exercise.
  • Adopt a diet rich in nitrate-containing vegetables like beets and leafy greens to support alternative NO pathways.
  • Regular aerobic exercise to stimulate eNOS expression and NO release.
  • Monitor blood pressure, lipid profile, folate, B12, and homocysteine with your provider.
1 effect allele — GT genotype

If your genotype is GT, you carry one effect allele and one non-effect allele. This intermediate status may slightly reduce NOS3 activity under stress, inflammation, or nutrient deficiency. Under normal conditions your NO production is likely adequate, but targeted support can help keep eNOS functioning well.

Recommended focus areas:

  • Maintain good folate and B vitamin status through diet or targeted supplementation.
  • Include antioxidant-rich foods and consider vitamin C around times of increased oxidative stress.
  • Incorporate nitrate-rich vegetables and arginine/citrulline sources into meals to support NO production.
  • Regular physical activity to boost eNOS activity and vascular resilience.
  • Routine monitoring of cardiovascular markers and folate/methylation status as indicated by your clinician.
0 effect alleles — GG genotype

If your genotype is GG, you carry two non-effect alleles and are associated with normal NOS3 enzyme activity. Your endothelial NO production is likely well supported, which benefits circulation, ammonia clearance, and methylation balance. Standard healthy-lifestyle practices will help maintain NO levels.

Good maintenance strategies:

  • Follow a balanced diet with folate-rich vegetables, nitrates from leafy greens and beets, and sources of arginine and citrulline.
  • Stay active with regular exercise to maintain eNOS function.
  • Keep antioxidant intake adequate through diet to prevent oxidative stress.
  • Regular checkups for blood pressure, lipids, and general metabolic health.

Other Considerations

  • Genetics is one piece of the picture. Lifestyle, diet, environment, and other genes also influence NO biology and cardiovascular risk.
  • If you have symptoms such as unexplained fatigue, poor exercise tolerance, persistent high blood pressure, or neurological concerns, discuss targeted evaluation with your healthcare provider.
  • Before starting any supplement or making major changes to your medication or diet, consult your healthcare provider to ensure safety and appropriateness for your overall health and current treatments.

PlexusDx provides education about genetic predispositions and does not provide medical advice. Always consult with your healthcare provider before making changes to your treatment, supplements, or lifestyle based on genetic information.