Maternal overnutrition impairs myocardial geometry and function in conjunction with proinflammatory activation in fetal sheep hearts

Abstract

Aim: Maternal overnutrition predisposes offspring to an increased prevalence of cardiovascular disease, yet the specific underlying mechanisms remain elusive.

Methods: This study examined the roles of inflammation and ferroptosis in driving fetal cardiac structural and functional alterations following maternal overnutrition. Multiparous ewes were fed either a control diet [100% of National Research Council (NRC) recommended requirements] or an overnutrition diet (150% of NRC requirement) from 60 days preconception until gestational day 135. Cardiac geometry, histomorphology, immune cell infiltration, cardiomyocyte function, intracellular Ca²⁺ handling, and expression of inflammatory and ferroptotic markers were assessed in fetal hearts.

Results: Despite comparable fetal crown-rump lengths and organ weights (e.g., brain and liver), fetuses from overnourished ewes exhibited significantly lower body and heart weights. Maternal overnutrition induced marked cardiac atrophy, interstitial fibrosis, lipid deposition, and oxidative damage, coupled with increased neutrophil and monocyte infiltration. At the cellular level, cardiomyocytes from overnourished fetuses exhibited impaired contractile and intracellular Ca²⁺ properties. Molecular profiling revealed that maternal overnutrition significantly upregulated proinflammatory markers (CD14, CD68, IL1A, IL1B, IL6, TLR4, and iNOS), and increased IκB phosphorylation (indicating NFκB activation). Concurrently, overnutrition suppressed IL18 and M-CSF expression, alongside the ferroptosis-defense proteins GPX4 and SLC7A11.

Conclusion: These findings demonstrate that maternal overnutrition creates a proinflammatory and ferroptosis-prone myocardial environment, resulting in pathological structural remodeling and functional impairment of fetal hearts. Our data suggest that targeting the inflammation-ferroptosis signaling may help to mitigate the developmental programming of cardiovascular disease.

Keywords

Maternal overnutrition / fetal hearts / inflammation / ferroptosis

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