Prevention of vascular dysfunction and arterial hypertension in mice generated by assisted reproductive technologies by addition of melatonin to culture media.
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.
Department of Cardiology and Clinical Research, University Hospital, Bern, Switzerland;
Emrush
E
Rexhaj
Department of Cardiology and Clinical Research, University Hospital, Bern, Switzerland;
Agim
A
Pireva
Department of Genetic and Laboratory Medicine and Swiss Center for Applied Human Toxicology, Geneva University Hospital, Geneva, Switzerland;
Ariane
A
Paoloni-Giacobino
Department of Cardiology and Clinical Research, University Hospital, Bern, Switzerland;
Yves
Y
Allemann
Department of Cardiology and Clinical Research, University Hospital, Bern, Switzerland;
David
D
Cerny
Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; and.
Pierre
P
Dessen
Department of Cardiology and Clinical Research, University Hospital, Bern, Switzerland; Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; and.
Claudio
C
Sartori
Department of Cardiology and Clinical Research, University Hospital, Bern, Switzerland; Facultad de Ciencias, Departamento de Biología, Universidad de Tarapacá, Arica, Chile.
Urs
U
Scherrer
Department of Cardiology and Clinical Research, University Hospital, Bern, Switzerland; stefano.rimoldi@insel.ch.
Stefano F
SF
Rimoldi
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D003470:Culture Media; D019175:DNA Methylation / Q000187:drug effects; D046149:Embryo Culture Techniques; D044127:Epigenesis, Genetic / Q000187:drug effects*; D006973:Hypertension / Q000517:prevention & control; D008550:Melatonin / Q000494:pharmacology*; D008638:Mesenteric Arteries / Q000187:drug effects*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects* / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects; D027724:Reproductive Techniques, Assisted; D014665:Vasodilator Agents / Q000494:pharmacology
D000975:Antioxidants; D003470:Culture Media; D014665:Vasodilator Agents; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D008550:Melatonin; D000109:Acetylcholine
arterial hypertension; endothelial dysfunction; epigenetic; in vitro fertilization; melatonin; nitric oxide