Abstract
Placental insufficiency is associated with fetal hypoglycemia, hypoxemia, and elevated plasma norepinephrine (NE) that become increasingly pronounced throughout the third trimester and contribute to intrauterine growth restriction (IUGR). This study evaluated the effect of fetal adrenal demedullation (AD) on growth and pancreatic endocrine cell mass. Placental insufficiency-induced IUGR was created by exposing pregnant ewes to elevated ambient temperatures during mid-gestation. Treatment groups consisted of control and IUGR fetuses with either surgical sham or AD at 98 days gestational age (dGA; term = 147 dGA), a time-point that precedes IUGR. Samples were collected at 134 dGA. IUGR-sham fetuses were hypoxemic, hypoglycemic, and hypoinsulinemic, and values were similar in IUGR-AD fetuses. Plasma NE concentrations were ~5-fold greater in IUGR-sham compared to control-sham, control-AD, and IUGR-AD fetuses. IUGR-sham and IUGR-AD fetuses weighed less than controls. Compared to IUGR-sham fetuses, IUGR-AD fetuses weighed more and asymmetrical organ growth was absent. Pancreatic β-cell mass and α-cell mass were lower in both IUGR-sham and IUGR-AD fetuses compared to controls, however, pancreatic endocrine cell mass relative to fetal mass was lower in IUGR-AD fetuses. These findings indicate that NE, independently of hypoxemia, hypoglycemia and hypoinsulinemia, influence growth and asymmetry of growth but not pancreatic endocrine cell mass in IUGR fetuses.
Highlights
Intrauterine growth restriction (IUGR) is often caused by placental insufficiency resulting in fetal hypoxemia and hypoglycemia, which elevate plasma catecholamines [1,2,3,4,5,6,7,8,9,10]
Expression of α2A-adrenergic receptor mRNA was greater in islets isolated from the intrauterine growth restriction (IUGR) fetus, which potentially facilitate the chronic inhibition of insulin, an anabolic hormone in the fetus [3,4,5,30,31]
IUGR-sham fetuses had lower plasma insulin and glucose concentrations compared to control-shams (Figure 1)
Summary
Intrauterine growth restriction (IUGR) is often caused by placental insufficiency resulting in fetal hypoxemia and hypoglycemia, which elevate plasma catecholamines [1,2,3,4,5,6,7,8,9,10]. NE is the major catecholamine secreted from the adrenal medulla due to low expression of phenylethanolamine N-methyltransferase (PNMT), an enzyme that converts NE to epinephrine [16]. Sympathetic neurons, such as the splanchnic nerve, contribute to plasma NE concentrations, the adrenal medulla has been shown to be primarily responsible for hypoxia-stimulated increases of NE and epinephrine in fetal plasma [13,17,18,19,20]. Previous work has shown that continuous infusion of epinephrine or NE for >7 days into normal sheep fetuses produced asymmetric fetal growth restriction and chronically lowered plasma insulin concentrations [17,32]. Insulin-independent NE actions have been associated with lower oxidative metabolism [20,30]
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