Restriction of placental function alters heart development in the sheep fetus

Abstract

Placental insufficiency, resulting in restriction of fetal substrate supply, is a major cause of intrauterine growth restriction (IUGR) and increased neonatal morbidity. Fetal adaptations to placental restriction maintain the growth of key organs, including the heart, but the impact of these adaptations on individual cardiomyocytes is unknown. Placental and hence fetal growth restriction was induced in fetal sheep by removing the majority of caruncles in the ewe before mating (placental restriction, PR). Vascular surgery was performed on 13 control and 11 PR fetuses at 110-125 days of gestation (term: 150 +/- 3 days). PR fetuses with a mean gestational Po(2) < 17 mmHg were defined as hypoxic. At postmortem (<135 or >135 days), fetal hearts were collected, and cardiomyocytes were isolated and fixed. Proliferating cardiomyocytes were counted by immunohistochemistry of Ki67 protein. Cardiomyocytes were stained with methylene blue to visualize the nuclei, and the proportion of mononucleated cells and length and width of cardiomyocytes were measured. PR resulted in chronic fetal hypoxia, IUGR, and elevated plasma cortisol concentrations. Although there was no difference in relative heart weights between control and PR fetuses, there was an increase in the proportion of mononucleated cardiomyocytes in PR fetuses. Whereas mononucleated and binucleated cardiomyocytes were smaller, the relative size of cardiomyocytes when expressed relative to heart weight was larger in PR compared with control fetuses. The increase in the relative proportion of mononucleated cardiomyocytes and the relative sparing of the growth of individual cardiomyocytes in the growth-restricted fetus are adaptations that may have long-term consequences for heart development in postnatal life.

Folate rescues lithium-, homocysteine- and Wnt3A-induced vertebrate cardiac anomalies

“…Thus, the echo data was essential to determine whether valve integrity had been functionally compromised and provided information on placental blood flow that related to the intrauterine growth restriction (IUGR) that we observed. IUGR is associated generally with effects on placental and heart development (Corstius et al, 2005;Morrison et al, 2007). Other studies have reported that Wnt-β-catenin signaling and HCy impact placental development (Kamudhamas et al, 2004;Mohamed et al, 2008); our results substantiate these observations.…”

Effect of Maternal Protein Restriction During Pregnancy and Lactation on the Number of Cardiomyocytes in the Postproliferative Weanling Rat Heart

“…However, this may not be the case following IUGR. Importantly, in this regard in the ovine model, where cardiomyocyte maturation resembles that in humans, we (Bubb et al, 2007) and others (Morrison et al, 2007) have shown delayed maturation of cardiomyocytes following induction of IUGR late in gestation. Hence, if this also applies to the human IUGR heart, it may be possible for ''catch-up'' hyperplasia to occur postnatally in a similar manner to that observed in the rodent heart.…”

“…Certainly, a reduction in the number of cardiomyocytes in early life could have an adverse impact on the heart's capacity for hypertrophy later in life. A significant reduction in the proportion of terminally differentiated cardiomyocytes has been shown in fetal sheep models of IUGR (Bubb et al, 2007;Morrison et al, 2007). In addition, recently, we have shown that the number of cardiomyocytes is significantly reduced at birth in rat offspring that had been exposed to maternal protein restriction (Corstius et al, 2005).…”

Impact of chronic hypoxemia on blood flow to the brain, heart, and adrenal gland in the late-gestation IUGR sheep fetus

“…In the present study, we have used a well-established model of chronic placental insufficiency, in which the majority of the uterine caruncles (potential placental attachment sites) are removed prior to pregnancy in the sheep (1,18,23,50,54,55), which results in placental and, hence, fetal growth restriction, as well as chronic hypoxemia, from as early as measured from 100 days gestation (GA) (77). The growth-restricted placental restriction (PR) fetus has a relatively larger brain and adrenal gland and higher circulating norepinephrine and cortisol concentrations compared with the normally grown fetus in late gestation (48,67,77).…”