Effects of Vitamin E on Vascular Endothelial Function: The Mysterious Relationship Between Single Intake and Combination

Disclaimer (Important)

This article summarizes research findings and does not recommend specific intake. Vitamin E is fat-soluble, and the risks of overdose (such as bleeding tendency) differ from water-soluble vitamins. Please consult a doctor if you have underlying conditions.

TL;DR (Conclusion First)

• Overall Trend: At the meta-analysis level, Vitamin E intake works in the direction of improving vascular endothelial function (FMD, etc.).
• Paradox: Interestingly, there are reports that “Vitamin E alone” shows a clearer improvement effect than “combination with Vitamin C” (complexity of interaction).
• Strong Subjects: Improvement reports are prominent under specific oxidative stress environments such as hemodialysis patients and type 1 diabetes.

Overview: Suggestions from Meta-analysis on “Single vs. Combination”

A systematic review/meta-analysis verifying the effects of Vitamin C and E (Ashor AW, et al. 2015) shows the following interesting trends:

1. Vitamin E alone: Significantly improves endothelial function.
2. Vitamin C alone: Significantly improves endothelial function.
3. Combination (C+E): Statistical significance disappears (or the effect weakens).

This suggests that it is not a simple addition where “the more antioxidants you add, the better”. It is possible that the recycling cycle of E radicals is complicatedly involved in the redox balance in the living body.

• Ashor AW, et al. Effect of vitamin C and vitamin E supplementation on endothelial function: a systematic review and meta-analysis (Br J Nutr. 2015) PubMed: https://pubmed.ncbi.nlm.nih.gov/25919436/

Key Findings by Pathology

1) Hemodialysis Patients: Reduction of Inflammation and Adhesion Factors

Dialysis patients due to renal failure are in a state of extremely high oxidative stress and chronic inflammation. Recent meta-analyses (Nguyen TTU, et al. Int J Mol Sci. 2021, etc.) have also confirmed that Vitamin E supplementation significantly reduces vascular adhesion factors (markers of endothelial damage) such as ICAM-1 and VCAM-1 in the blood. It is expected to have an effect of suppressing “vascular inflammation” at the molecular level, not just physical vasodilation response.

2) Diabetes: Another Route Called PKC Inhibition

In a hyperglycemic state, an enzyme called protein kinase C (PKC) is activated, which causes vascular damage. Vitamin E is known to have an action of inhibiting this PKC activity, independent of its antioxidant effect.

• Type 1 Diabetes: There are reports that 1000 IU/day of Vitamin E improved retinal blood flow and endothelial function in young patients (Bursell SE, et al. Diabetes Care. 1999; Skyrme-Jones RA, et al. JACC. 2000).
• Note: On the other hand, there are reports that long-term, high-dose (e.g., 1800 IU/day) administration worsened endothelial function, so dosage setting is severe.

Deep Dive into Mechanism: The Decisive Difference Between C and E

Both Vitamin C and E are known as “antioxidant vitamins”, but the place and method they work are clearly different.

1. Different “Places” to Protect (Water-soluble vs. Fat-soluble)

• Vitamin C (Water-soluble): Works in places with “water” such as cytoplasm and plasma. It plays a role in directly eliminating reactive oxygen species (superoxide, etc.) and returning oxidized Vitamin E to its original state.
• Vitamin E (Fat-soluble): Dives into places with “fat” such as cell membranes and LDL (lipoproteins). Here, it plays an extremely important role of breaking the chain of lipid peroxidation (Chain-breaking). It is, so to speak, a “castle wall guard” that prevents cell membranes from becoming tattered by oxidation.

2. Vitamin E’s Unique “PKC Inhibitory Action”

Vitamin E (especially $\alpha$-tocopherol) has an important function independent of its antioxidant effect. That is inhibition of Protein Kinase C (PKC) activity.

• Hyperglycemia/Oxidative Stress $\rightarrow$ PKC Activation $\rightarrow$ Decreased eNOS (NO synthase) function $\rightarrow$ Validation Failure In response to this vicious cycle, Vitamin E protects the ability to produce NO by calming PKC. This is attracting particular attention as a prevention mechanism for diabetic vascular complications.

3. Collaboration between C and E (Recycling of Vitamin E)

When Vitamin E eliminates reactive oxygen species, it becomes an oxidized form called “tocopheryl radical”. There is a recycling system where Vitamin C donates electrons to return (reduce) it to the original Vitamin E. Theoretically, “taking C and E together seems strongest”, but the reason why the “combination effect is weak/non-existent” in the aforementioned meta-analysis is speculated to be because this balance is disrupted (disturbance of Redox balance due to excessive reduction) or complex interactions occur at clinical dosages.

VascularEvidenceJapan Perspective: Issues to Watch Next

1. Natural vs. Synthetic: Vitamin E (d-α-tocopherol, etc.) has many isomers. The fact that different forms are used depending on the study makes interpretation difficult.
2. Effect on “Healthy People”: In healthy subjects with low baseline oxidative stress, the merit of additional administration (FMD improvement) is likely limited.
3. Balance with Bleeding Risk: Since Vitamin E also has an antiplatelet effect, it is necessary to weigh the merit of improving endothelial function against the demerit of bleeding risk.

References

• Ashor AW, et al. Effect of vitamin C and vitamin E supplementation on endothelial function: a systematic review and meta-analysis (Br J Nutr. 2015) PubMed: https://pubmed.ncbi.nlm.nih.gov/25919436/
• Nguyen TTU, et al. Beneficial Effects of Vitamin E Supplementation on Endothelial Dysfunction… in Patients Receiving Hemodialysis (Int J Mol Sci. 2021) PubMed: https://pubmed.ncbi.nlm.nih.gov/34769353/
• Bursell SE, et al. High-dose vitamin E supplementation normalizes retinal blood flow and creatinine clearance in patients with type 1 diabetes (Diabetes Care. 1999) PubMed: https://pubmed.ncbi.nlm.nih.gov/10480765/
• Skyrme-Jones RA, et al. Vitamin E supplementation improves endothelial function in type I diabetes mellitus (J Am Coll Cardiol. 2000) PubMed: https://pubmed.ncbi.nlm.nih.gov/10898419/
• Economides PA, et al. The effect of vitamin E on endothelial function of micro- and macrocirculation and left ventricular function in type 1 and type 2 diabetic patients (Diabetes. 2005) DOI: https://doi.org/10.2337/DIABETES.54.1.204

Related Articles

• Does Vitamin C Improve Endothelial Function? Reading Short-term and Long-term Evidence from an FMD Perspective
• Why Does Vitamin C Improve Vascular Endothelial Function? Deep Dive into Molecular Mechanisms