Intrauterine growth restriction is associated with cardiac ultrastructural and gene expression changes related to the energetic metabolism in a rabbit model

Abstract

Intrauterine growth restriction (IUGR) affects 7-10% of pregnancies and is associated with cardiovascular remodeling and dysfunction, which persists into adulthood. The underlying subcellular remodeling and cardiovascular programming events are still poorly documented. Cardiac muscle is central in the fetal adaptive mechanism to IUGR given its high energetic demands. The energetic homeostasis depends on the correct interaction of several molecular pathways and the adequate arrangement of intracellular energetic units (ICEUs), where mitochondria interact with the contractile machinery and the main cardiac ATPases to enable a quick and efficient energy transfer. We studied subcellular cardiac adaptations to IUGR in an experimental rabbit model. We evaluated the ultrastructure of ICEUs with transmission electron microscopy and observed an altered spatial arrangement in IUGR, with significant increases in cytosolic space between mitochondria and myofilaments. A global decrease of mitochondrial density was also observed. In addition, we conducted a global gene expression profile by advanced bioinformatics tools to assess the expression of genes involved in the cardiomyocyte energetic metabolism and identified four gene modules with a coordinated over-representation in IUGR: oxygen homeostasis (GO: 0032364), mitochondrial respiratory chain complex I (GO:0005747), oxidative phosphorylation (GO: 0006119), and NADH dehydrogenase activity (GO:0003954). These findings might contribute to changes in energetic homeostasis in IUGR. The potential persistence and role of these changes in long-term cardiovascular programming deserves further investigation.

Cardiac and placental mitochondrial characterization in a rabbit model of intrauterine growth restriction

“…However, disease modeling and investigation in cardiac or placental target tissues are lacking. It is important to note that in the present study, offspring with induced IUGR showed altered biometric measures by significant decrease in birth weight, accompanied by a reduction in heart and placenta, as previously reported (14). Thus, organ to body weight measures were preserved due to global and proportioned organ and body mass reduction.…”

“…For this reason, our group developed a rabbit model to study IUGR in which cardiovascular remodeling with altered spatial arrangement of intracellular energetic units was evidenced by microscopy in the offspring (12, 13), also reflecting the hemodynamic alterations found in newborns of IUGR pregnancies. The global gene expression profile of the hearts of offspring in this IUGR-rabbit model showed alterations in different pathways, all of which converged to mitochondria, including oxygen homeostasis, mitochondrial respiratory chain (MRC) complex I, oxidative phosphorylation and NADH dehydrogenase activity (10,14). Alternative animal models of IUGR have been developed consisting in carunclectomy, uterine artery ligation, uterine space restriction, caloric restriction or hypoxic conditions, among other procedures, in different species of animals (mainly sheep, pigs or rats models) (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26).…”

Descriptive analysis of different phenotypes of cardiac remodeling in fetal growth restriction

“…As a result, hypertrophy will be induced to increase contractility, as well as to decrease local wall stress, and cardiomegaly might develop as a response to persistent volume overload. This response of early‐onset FGR is consistent with reports in the 1990s (mainly focused on early‐onset FGR) suggesting cardiomegaly and a ‘heart‐sparing effect’ as a typical sign of FGR, with more recent studies and data from experimental models (usually mimicking severe forms) demonstrating increased myocardial wall thickness and more spherical ventricles in FGR cases. Theoretical inconsistencies with previous studies suggesting smaller and non‐hypertrophic hearts could be explained by the lack of normalization for body size, the definition of FGR used (mixing truly growth‐restricted and constitutionally small fetuses) and reporting means/medians among groups which are more influenced by the values of the extreme and more prevalent cases.…”

Oxidative damage and nitric oxide synthase induction by surgical uteroplacental circulation restriction in the rabbit fetal heart

“…We did not test the hypoxic state in the fetal heart at culling. Interestingly, several authors have described a compensatory mechanism, which results in increased blood flow to vital organs such as the brain, heart, and adrenal gland during fetal ischemia. Using our IUGR model, we recently described significant deregulation of NOS (eNOS inactivation and iNOS induction) and damage by oxidative stress in fetal growth restricted rabbits .…”