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Title

Prevention of vascular dysfunction and arterial hypertension in mice generated by assisted reproductive technologies by addition of melatonin to culture media

Authors
Rexhaj, Emrush
Pireva, Agim
Allemann, Yves
Cerny, David
Dessen, Pierre
Sartori, Claudio
Scherrer, Urs
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Published in American Journal of Physiology. Heart and Circulatory Physiology. 2015, vol. 309, no. 7, p. H1151-H1156
Abstract Assisted reproductive technologies (ART) induce vascular dysfunction in humans and mice. In mice, ART-induced vascular dysfunction is related to epigenetic alteration of the endothelial nitric oxide synthase (eNOS) gene, resulting in decreased vascular eNOS expression and nitrite/nitrate synthesis. Melatonin is involved in epigenetic regulation, and its administration to sterile women improves the success rate of ART. We hypothesized that addition of melatonin to culture media may prevent ART-induced epigenetic and cardiovascular alterations in mice. We, therefore, assessed mesenteric-artery responses to acetylcholine and arterial blood pressure, together with DNA methylation of the eNOS gene promoter in vascular tissue and nitric oxide plasma concentration in 12-wk-old ART mice generated with and without addition of melatonin to culture media and in control mice. As expected, acetylcholine-induced mesenteric-artery dilation was impaired (P = 0.008 vs. control) and mean arterial blood pressure increased (109.5 ± 3.8 vs. 104.0 ± 4.7 mmHg, P = 0.002, ART vs. control) in ART compared with control mice. These alterations were associated with altered DNA methylation of the eNOS gene promoter (P < 0.001 vs. control) and decreased plasma nitric oxide concentration (10.1 ± 11.1 vs. 29.5 ± 8.0 μM) (P < 0.001 ART vs. control). Addition of melatonin (10(-6) M) to culture media prevented eNOS dysmethylation (P = 0.005, vs. ART + vehicle), normalized nitric oxide plasma concentration (23.1 ± 14.6 μM, P = 0.002 vs. ART + vehicle) and mesentery-artery responsiveness to acetylcholine (P < 0.008 vs. ART + vehicle), and prevented arterial hypertension (104.6 ± 3.4 mmHg, P < 0.003 vs. ART + vehicle). These findings provide proof of principle that modification of culture media prevents ART-induced vascular dysfunction. We speculate that this approach will also allow preventing ART-induced premature atherosclerosis in humans.
Keywords Acetylcholine/pharmacologyAnimalsAntioxidants/pharmacologyBlood Pressure/drug effectsCulture MediaDNA Methylation/drug effectsEmbryo Culture TechniquesEpigenesis, Genetic/drug effectsHypertension/prevention & controlMelatonin/pharmacologyMesenteric Arteries/drug effectsMiceNitric Oxide/metabolismNitric Oxide Synthase Type III/drug effects/geneticsPromoter Regions, Genetic/drug effectsReproductive Techniques, AssistedVasodilator Agents/pharmacology
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PMID: 26276822
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Research group Groupe Giacobino Ariane (génétique) (923)
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REXHAJ, Emrush et al. Prevention of vascular dysfunction and arterial hypertension in mice generated by assisted reproductive technologies by addition of melatonin to culture media. In: American Journal of Physiology. Heart and Circulatory Physiology, 2015, vol. 309, n° 7, p. H1151-H1156. https://archive-ouverte.unige.ch/unige:92438

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Deposited on : 2017-03-08

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