Foetal growth has been proposed to influence cardiovascular health in adulthood, a process referred to as foetal programming. Indeed, intrauterine growth restriction in animal models alters heart size and cardiomyocyte number in the perinatal period, yet the consequences for the adult or challenged heart are largely unknown. The aim of this study was to elucidate postnatal myocardial growth pattern, left ventricular function, and stress response in the adult heart after neonatal cardiac hypoplasia in mice. Utilizing a new mouse model of impaired cardiac development leading to fully functional but hypoplastic hearts at birth, we show that myocardial mass is normalized until early adulthood by accelerated physiological cardiomyocyte hypertrophy. Compensatory hypertrophy, however, cannot be maintained upon ageing, resulting in reduced organ size without maladaptive myocardial remodelling. Angiotensin II stress revealed aberrant cardiomyocyte growth kinetics in adult hearts after neonatal hypoplasia compared with normally developed controls, characterized by reversible overshooting hypertrophy. This exaggerated growth mainly depends on STAT3, whose inhibition during angiotensin II treatment reduces left ventricular mass in both groups but causes contractile dysfunction in developmentally impaired hearts only. Whereas JAK/STAT3 inhibition reduces cardiomyocyte cross-sectional area in the latter, it prevents fibrosis in control hearts, indicating fundamentally different mechanisms of action. Impaired prenatal development leading to neonatal cardiac hypoplasia alters postnatal cardiac growth and stress response in vivo, thereby linking foetal programming to organ size control in the heart.
Summary Epidemiological studies have shown an association between low birthweight and adult disease development with transmission to subsequent generations. The aim of the present study was to examine the effect of intrauterine growth restriction in rats, induced by uteroplacental insufficiency, on cardiac structure, number, size, nuclearity, and adult blood pressure in first (F1) and second (F2) generation male offspring. Uteroplacental insufficiency or sham surgery was induced in F0 Wistar‐Kyoto pregnant rats in late gestation giving rise to F1 restricted and control offspring, respectively. F1 control and restricted females were mated with normal males, resulting in F2 control and restricted offspring, respectively. F1 restricted male offspring were significantly lighter at birth ( P < 0.05), but there were no differences in birthweight of F2 offspring. Left ventricular weights and volumes were significantly increased ( P < 0.05) in F1 and F2 restricted offspring at day 35. Left ventricular cardiomyocyte number was not different in F1 and F2 restricted offspring. At 6 months‐of‐age, F1 and F2 restricted offspring had elevated blood pressure (8–15 mmHg, P < 0.05). Our findings demonstrate the emergence of left ventricular hypertrophy and hypertension, with no change in cardiomyocyte number, in F1 restricted male offspring, and this was transmitted to the F2 offspring. The findings support transgenerational programming effects.
High alcohol consumption during pregnancy leads to deleterious effects on fetal cardiac structure and it also affects cardiomyocyte growth and maturation. This study aimed to determine whether low levels of maternal alcohol consumption are also detrimental to cardiomyocyte and cardiac growth in the early life of offspring and whether cardiac structure and function in adulthood is affected. Pregnant Sprague–Dawley rat dams were fed a control or 6% (volume/volume) liquid-based ethanol supplemented (isocaloric) diet throughout gestation. At embryonic day 20, the expression of genes involved in cardiac development was analyzed using Real-time PCR. At postnatal day 30, cardiomyocyte number, size, and nuclearity in the left ventricle (LV) were determined stereologically. In 8-month-old offspring, LV fibrosis and cardiac function (by echocardiography) were examined. Maternal ethanol consumption did not alter gene expression of the cardiac growth factors in the fetus or cardiomyocyte number in weanling offspring. However, at 8 months, there were significant increases in LV anterior and posterior wall thickness during diastole in ethanol-exposed offspring (P = 0.037 and P = 0.024, respectively), indicative of left ventricular hypertrophy; this was accompanied by a significant increase in fibrosis. Additionally, maximal aortic flow velocity was significantly decreased in ethanol-exposed offspring (P = 0.035). In conclusion, although there were no detectable early-life differences in cardiac and cardiomyocyte growth in animals exposed to a chronic low dose of ethanol during gestation, there were clearly deleterious outcomes by adulthood. This suggests that even relatively low doses of alcohol consumed during pregnancy can be detrimental to long-term cardiac health in the offspring.
Remarkable growth plasticity enables the prenatal mammalian heart to counteract various unfavorable intrauterine conditions and build a functional and normally sized organ at birth. We have recently shown that the murine embryonic and fetal heart has a substantial regenerative capacity in response to tissue mosaicism for mitochondrial dysfunction caused by heart specific inactivation of the X-linked holocytochrome c synthase (Hccs) gene. In heterozygous Hccs knockout (Hccs+/-) embryos, hyperproliferation of healthy cardiomyocytes compensates for the functional loss of 50% cardiac cells, ensuring formation of a functional heart at birth. However, we hypothesized that embryonic heart regeneration alters peri- and postnatal cardiac growth mechanisms. Indeed, neonatal Hccs+/- hearts are hypoplastic containing a reduced number of cardiomyocytes, whereas in adult Hccs+/- hearts compensatory cellular hypertrophy normalizes morphology and size. We aimed at identifying postnatal adaptive growth mechanisms utilized by the hypoplastic Hccs+/- heart to restore organ size and allow normal heart function throughout lifetime. Microarray RNA expression analyses revealed numerous genes involved in amino acid metabolism, protein homeostasis and translational control being differentially expressed in neonatal Hccs+/- hearts. Subsequently, western blot analyses evidenced significantly increased mammalian target of rapamycin (mTOR) activity, a major regulator of translation and cell growth, in Hccs+/- hearts compared to controls. To clarify its role for compensatory growth of the Hccs+/- myocardium, we inhibited mTOR in fetal and neonatal mice by rapamycin treatment of pregnant dams. Rapamycin treated Hccs+/- neonates (n=17) show significantly reduced heart weight to body weight ratios compared to controls (n=18) or vehicle treated animals (n=12 and n=13). Furthermore, Hccs+/- hearts after prenatal mTOR inhibition are morphologically characterized by developmental delay. In conclusion, our data revealed mTOR being essential for normal as well as compensatory growth of the fetal heart. Thus, metabolic adaptations converging on mTOR might be required to prevent postnatal heart disease after impaired intrauterine development.
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