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Physiology and Biochemistry

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

Abstract

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.

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Fig. 1: DNA methylation profile of mesenteric arteries of 4-month old OMO males and females.
Fig. 2: Vascular reactivity of mesenteric arteries in CMO and OMO males (top panel) and females (bottom panel) at 4 months of age.
Fig. 3: Analysis of vasoactive pathways involved in the endothelium-induced relaxation of mesenteric arteries in CMO and OMO males (top panel) and females (bottom panel) at 4 months of age.
Fig. 4: White adipose tissue analysis of CMO and OMO males and females at 4 months of age.

Data availability

The data, methods used in the analysis, and materials used to conduct the study are available from the corresponding author upon reasonable request. Requests to access the datasets should be directed to celine.fassot@inserm.fr.

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Acknowledgements

We thank Dr Françoise Larcher and Dr Khaled Messaoudi (Biochemical Department, University Hospital of Angers, France) who had performed plasma metabolic measurements, and SCAHU (an animal facility in Angers) which takes care of the animals.

Funding

This project was funded by “Fondation de France” (grant No. 00075806 “Influence of maternal obesity on fetal programming of cardiovascular abnormalities”). CP received a grant from the University of Angers to support her Ph.D.

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Correspondence to Céline Fassot.

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Payen, C., Guillot, A., Paillat, L. et al. Pathophysiological adaptations of resistance arteries in rat offspring exposed in utero to maternal obesity is associated with sex-specific epigenetic alterations. Int J Obes (2021). https://doi.org/10.1038/s41366-021-00777-7

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