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Effect of hyperhomocystinemia and hypertension on endothelial function in methylenetetrahydrofolate
Agostino Virdis1, Marc Iglarz, Mario Fritsch Neves
1Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada.
Insights
Hyperhomocystinemia impairs vascular function in mice, causing endothelial dysfunction. Angiotensin II worsens these effects and causes structural changes, suggesting additive risks.
Area of Science:
- Cardiovascular Biology
- Vascular Physiology
- Metabolic Disease Research
Background:
- Hyperhomocysteinemia is linked to endothelial dysfunction and cardiovascular disease.
- Methylenetetrahydrofolate reductase (Mthfr) deficiency leads to elevated homocysteine levels.
- Angiotensin II (Ang II) plays a critical role in regulating blood pressure and vascular health.
Purpose of the Study:
- To investigate the combined effects of hyperhomocysteinemia and Ang II on vascular function and structure.
- To elucidate the mechanisms underlying endothelial dysfunction in Mthfr+/- mice.
Main Methods:
- Utilized methylenetetrahydrofolate reductase knockout (Mthfr+/-) mice and wild-type controls (Mthfr+/+).
- Administered Ang II or saline via subcutaneous infusion for 14 days.
- Assessed vascular function using a pressurized myograph to measure artery relaxation responses to acetylcholine and bradykinin.
- Measured blood pressure, vascular NADPH oxidase and xanthine oxidase activity, and superoxide production.
Main Results:
- Ang II increased blood pressure similarly in both Mthfr+/- and Mthfr+/+ mice.
- Endothelial-dependent relaxations were impaired in Mthfr+/- mice and further blunted by Ang II infusion.
- Ang II infusion increased media-to-lumen ratio and NADPH oxidase activity, indicating vascular structural changes and oxidative stress.
- Reduced nitric oxide bioavailability due to uncoupled nitric oxide synthase was identified as a key factor in endothelial dysfunction.
Conclusions:
- Mthfr+/- mice exhibit endothelial dysfunction, likely due to reduced nitric oxide bioavailability from oxidative stress.
- Concurrent Ang II-induced hypertension exacerbates endothelial dysfunction and induces vascular structural alterations.
- These findings highlight the additive adverse effects of hyperhomocysteinemia and Ang II-dependent hypertension on vascular health.
Objective:
We evaluated the effect of hyperhomocystinemia and angiotensin (Ang) II on vascular function and structure in methylenetetrahydrofolate reductase knockout mice (Mthfr+/-).
Methods And Results:
Mthfr+/- and controls (Mthfr+/+) received Ang II (400 ng/kg per min SC) or saline (14 days). Blood pressure, similar in Mthfr+/- and Mthfr+/+, was increased by Ang II. Acetylcholine- and bradykinin-induced relaxations were impaired in mesenteric resistance arteries (pressurized myograph) in Mthfr+/- and in Ang II-infused Mthfr+/+ mice and additionally blunted in Ang II-infused Mthfr+/- mice. The inhibition by L-NAME on acetylcholine was reduced in Mthfr+/- and in Ang II-Mthfr+/+ and absent in Ang II-Mthfr+/- mice. In these groups, vitamin C improved the response to acetylcholine and restored the inhibition by L-NAME. The media to lumen ratio of small arteries, similar in Mthfr+/- and Mthfr+/+, was increased by Ang II. Vascular NADPH oxidase activity, similar in Mthfr+/- and Mthfr+/+, increased after Ang II infusion. Vascular xanthine oxidase activity was also similar in Mthfr+/- and Mthfr+/+. Superoxide production in the aorta was reduced by sepiapterin and by L-NAME, suggesting that reduced bioavailability of tetrahydrobiopterin and uncoupling of nitric oxide synthase were the origin of increased reactive oxygen species in this model.
Conclusions:
Mthfr+/- mice show endothelial dysfunction of mesenteric vessels probably attributable to a reduced nitric oxide bioavailability caused by oxidative excess due to uncoupling of nitric oxide synthase without vascular structural alterations. Concurrent Ang II-induced hypertension additionally reduced nitric oxide, increased NADPH oxidase activity, and induced structural alterations. Our findings suggest additive adverse effect of Ang II-dependent hypertension and hyperhomocystinemia on endothelial function.
