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Updated: Oct 29, 2025
Fetal Echocardiography and Pulsed-wave Doppler Ultrasound in a Rabbit Model of Intrauterine Growth Restriction
Published on: June 29, 2013
Fetal Cardiac Lipid Sensing Triggers an Early and Sex-related Metabolic Energy Switch in Intrauterine Growth
Loïze Maréchal1,2, Benoit Sicotte1, Véronique Caron2
1Department of Pharmacology & Physiology, Faculty of Medicine, Université de Montréal, Montreal, Quebec H3T 1J4, Canada.
Insights
Intrauterine growth restriction (IUGR) causes early heart metabolic changes, particularly in females. Specific fatty acids activate pathways, suggesting a sex-related epigenetic switch in fetal energy use.
Area of Science:
- Cardiovascular Biology
- Metabolic Disorders
- Developmental Biology
Background:
- Intrauterine growth restriction (IUGR) is linked to later-life cardiometabolic issues.
- The fetal heart's metabolic adaptation to adverse conditions is not fully understood.
Purpose of the Study:
- To investigate cardiac metabolic changes in IUGR fetuses.
- To explore the mechanisms of energy expenditure and their regulation in IUGR.
Main Methods:
- Utilized an animal model of uteroplacental insufficiency-induced IUGR.
- Analyzed fetal cardiac tissue for mitochondrial function, gene expression, and lipid profiles.
- Performed transcriptional assays and epigenetic analysis.
Main Results:
- IUGR fetuses showed altered fatty acid and peroxisomal beta-oxidation gene expression.
- Sexual dimorphism was observed, with enhanced mitochondrial respiration and ATP production in female IUGR cardiomyocytes.
- Accumulation of specific long-chain fatty acids (LCFAs) activated PPARα, with epigenetic modifications noted.
Conclusions:
- IUGR induces premature, sex-specific cardiac metabolic remodeling.
- Specific LCFAs may serve as early indicators of IUGR's metabolic consequences.
Context:
Intrauterine growth restriction (IUGR) is an immediate outcome of an adverse womb environment, exposing newborns to developing cardiometabolic disorders later in life.
Objective:
This study investigates the cardiac metabolic consequences and underlying mechanism of energy expenditure in developing fetuses under conditions of IUGR.
Methods:
Using an animal model of IUGR characterized by uteroplacental vascular insufficiency, mitochondrial function, gene profiling, lipidomic analysis, and transcriptional assay were determined in fetal cardiac tissue and cardiomyocytes.
Results:
IUGR fetuses exhibited an upregulation of key genes associated with fatty acid breakdown and β-oxidation (Acadvl, Acadl, Acaa2), and mitochondrial carnitine shuttle (Cpt1a, Cpt2), instigating a metabolic gene reprogramming in the heart. Induction of Ech1, Acox1, Acox3, Acsl1, and Pex11a indicated a coordinated interplay with peroxisomal β-oxidation and biogenesis mainly observed in females, suggesting sexual dimorphism in peroxisomal activation. Concurring with the sex-related changes, mitochondrial respiration rates were stronger in IUGR female fetal cardiomyocytes, accounting for enhanced adenosine 5'-triphosphate production. Mitochondrial biogenesis was induced in fetal hearts with elevated expression of Ppargc1a transcript specifically in IUGR females. Lipidomic analysis identified the accumulation of arachidonic, eicosapentaenoic, and docosapentaenoic polyunsaturated long-chain fatty acids (LCFAs) in IUGR fetal hearts, which leads to nuclear receptor peroxisome proliferator-activated receptor α (PPARα) transcriptional activation in cardiomyocytes. Also, the enrichment of H3K27ac chromatin marks to PPARα-responsive metabolic genes in IUGR fetal hearts outlines an epigenetic control in the early metabolic energy switch.
Conclusion:
This study describes a premature and sex-related remodeling of cardiac metabolism in response to an unfavorable intrauterine environment, with specific LCFAs that may serve as predictive effectors leading to IUGR.
