Pathophysiological adaptations of resistance arteries in rat offspring exposed in utero to maternal obesity is associated with sex-specific epigenetic alterations

• Published in: International Journal of Obesity 2021-05, Vol.45 (5), p.1074-1085
• Main Authors: Payen, Cyrielle, Guillot, Abigaëlle, Paillat, Lily, Fothi, Abel, Dib, Abdallah, Bourreau, Jennifer, Schmitt, Françoise, Loufrani, Laurent, Aranyi, Tamas, Henrion, Daniel, Munier, Mathilde, Fassot, Céline
• Format: Article
• Language: English
• Subjects: 101/1; 631/443/592/75; 64; 692/699/1702/393; Adaptation; Adipose tissue; Animals; Arteries; Bisulfite; Blood flow; Blood vessels; Cardiovascular diseases; Collagen; Collagen - genetics; Complications and side effects; Diet, High-Fat; DNA Methylation; Endothelium; Endothelium, Vascular - physiopathology; Epidemiology; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Exposure; Female; Fetus; Fetuses; Food and Nutrition; Genetic aspects; Glucose tolerance; Growth; Health aspects; Health Promotion and Disease Prevention; Histomorphometry; Insulin; Internal Medicine; Life Sciences; Lipids; Male; Matrix metalloproteinase; Matrix metalloproteinases; Matrix Metalloproteinases - genetics; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolic disorders; Methylation; Obesity; Obesity, Maternal - physiopathology; Offspring; Perturbation; Potassium channels; Potassium Channels - genetics; Pregnancy; Prenatal Exposure Delayed Effects - physiopathology; Prenatal influences; Public Health; Rats; Rats, Sprague-Dawley; Risk factors; Sex Factors; Tissue analysis; Vascular Resistance; Vasodilation; Veins & arteries
• ISSN: 0307-0565; 1476-5497; 0307-0565
• DOI: 10.1038/s41366-021-00777-7

Background/objectives Maternal obesity impacts vascular functions linked to metabolic disorders in offspring, leading to cardiovascular diseases during adulthood. Even if the relation between prenatal conditioning of cardiovascular diseases by maternal obesity and vascular function begins to be documented, little is known about resistance arteries. They are of particular interest because of their specific role in the regulation of local blood flow. Then our study aims to determine if maternal obesity can directly program fetal vascular dysfunction of resistance arteries, independently of metabolic disorders. Methods With a model of rats exposed in utero to mild maternal diet-induced obesity (OMO), we investigated third-order mesenteric arteries of 4-month old rats in absence of metabolic disorders. The methylation profile of these vessels was determined by reduced representation bisulfite sequencing (RRBS). Vascular structure and reactivity were investigated using histomorphometry analysis and wire-myography. The metabolic function was evaluated by insulin and glucose tolerance tests, plasma lipid profile, and adipose tissue analysis. Results At 4 months of age, small mesenteric arteries of OMO presented specific epigenetic modulations of matrix metalloproteinases (MMPs), collagens, and potassium channels genes in association with an outward remodeling and perturbations in the endothelium-dependent vasodilation pathways (greater contribution of EDHFs pathway in OMO males compared to control rats, and greater implication of PGI 2 in OMO females compared to control rats). These vascular modifications were detected in absence of metabolic disorders. Conclusions Our study reports a specific methylation profile of resistance arteries associated with vascular remodeling and vasodilation balance perturbations in offspring exposed in utero to maternal obesity, in absence of metabolic dysfunctions.