Fetal glucose availability: a key regulator of the metabolic, hormonal and contractility profiles of the fetal sheep heart.

There is an association between fetal growth restriction (FGR) and a poor lifetime cardiac health trajectory. Defining the underlying mechanisms will aid in developing interventions to decrease the contribution of FGR-born offspring to the global burden of cardiovascular disease. One cause of FGR is maternal undernutrition. In late-gestation undernutrition (LGUN) fetal glucose supply, a main energy source for the fetal heart, is reduced. This may be a key contributor to altered fetal cardiac development; thus restoration of fetal glucose availability in the LGUN setting may be a viable target for intervention. To investigate the role of glucose availability in fetal heart development, we utilized an established pregnant sheep model of LGUN (50% global nutrient restriction) with or without a continuous intrafetal glucose infusion. LGUN reduced fetal plasma glucose concentrations, resulting in brain sparing that was normalized by intrafetal glucose infusion. LGUN decreased the protein abundance of oxidative phosphorylation complexes 1 and 3; however glucose infusion returned complex 3 abundance to that of controls. LGUN increased the phosphorylation of contractility and hypertrophy marker CAMKII, which was associated with increased left ventricular cardiac output; however intrafetal glucose infusion normalized CAMKII. Our findings demonstrate that glucose plays a specific role in regulating cardiac development in utero, highlighting the importance of adequate maternal nutrition in late gestation. KEY POINTS: Maternal late-gestation undernutrition (LGUN) reduces fetal plasma glucose concentrations. To investigate the role of glucose availability in fetal left ventricle (LV) development, we assessed whether LGUN-induced alterations in the contractility, metabolic and hormonal profiles can be ameliorated in LGUN fetuses receiving glucose infusion (LGUN+G). Relative brain weight was increased in LGUN compared to controls and restored in LGUN+G despite fetal glucose infusion only partially normalizing fetal plasma glucose concentrations to that of controls. LGUN decreased cardiac oxidative phosphorylation (OXPHOS)complex 1 and 3 abundance, and LGUN+G restored complex 3 to that of controls. LGUN increased the activation of the contractility marker, Ca2+/calmodulin-dependent protein kinase II (p-CAMKII), but restored in LGUN+G. The magnetic resonance imaging measure of the LV cardiac output was positively correlated with p-CAMKII expression in LGUN. This study highlights the role of in utero glucose availability in regulating the abundance of fetal LV OXPHOS complex 3 and CAMKII activation in utero.