Search

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 PGI2 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.

Obesity in women of childbearing age is of particular concern since there is overwhelming evidence that being born to an obese mother increases the risk for the child of developing metabolic (obesity, insulin resistance) and cardiovascular (vascular dysfunction) disorders in later life. These findings suggest that the nutritional stress associated with maternal obesity has an impact on the longterm health of the offspring and could impact directly the fetal vascular function. However, current studies use animals in which vascular dysfunction and metabolic disorders are present simultaneously. Using a model of rats exposed in utero to maternal obesity, we aimed to determine if maternal obesity was able to directly re-program fetal vascular function or if development of such dysfunction was linked to metabolic abnormalities in offspring. Obese female rats (under hight-fat diet) were crossed with non-obese males. The metabolic status of male offspring from obese mothers (OMO) and mothers controls (CMO) was evaluated immediately after weaning (21j) and 2 months later by tolerance tests to insulin (ITT) and glucose (GTT), and plasmatic lipid profile. Vascular reactivity of the aorta was evaluated by myography (vascular reactivity in response to pharmacological agents). At weaning, GTT, ITT, plasmatic lipid profile as well as vascular reactivity of OMO were similar to those of CMO. At 3 months of age, although metabolic and lipid profiles are not modified, endotheliumdependant vasodilation was altered in OMO compared to CMO (acetylcholine dose-response curve EC 50 : 2,46E-06±5,26E-07 vs 3,60E-07±5,01E-08 for OMO and CMO respectively, p The author hereby declares no conflict of interest