Sarah M. Estrada

Long-Term Impact of Intrauterine Neuroinflammation and Treatment with Magnesium Sulphate and Betamethasone: Sex-Specific Differences in a Preterm Labor Murine Model

Preterm infants are at significantly increased risk for lifelong neurodevelopmental disability with male offspring disproportionately affected. Corticosteroids (such as betamethasone) and magnesium sulphate (MgSO4) are administered to women in preterm labor to reduce neurologic morbidity. Despite widespread use of MgSO4 in clinical practice, its effects on adult offspring are not well known nor have sex-specific differences in therapeutic response been explored. The objective of our study was to examine the long-term effects of perinatal neuroinflammation and the effectiveness of prenatal MgSO4/betamethasone treatments between males and females in a murine model via histologic and expression analyses. Our results demonstrate that male but not female offspring exposed to intrauterine inflammation demonstrated impaired performance in neurodevelopmental testing in early life assessed via negative geotaxis, while those exposed to injury plus treatment fared better. Histologic analysis of adult male brains identified a significant reduction in hippocampal neural density in the injured group compared to controls. Evaluation of key neural markers via qRT-PCR demonstrated more profound differences in gene expression in adult males exposed to injury and treatment compared to female offspring, which largely showed resistance to injury. Prenatal treatment with MgSO4/betamethasone confers long-term benefits beyond cerebral palsy prevention with sex-specific differences in response.

Evaluating maternal hyperglycemic exposure and fetal placental arterial dysfunction in a dual cotyledon, dual perfusion model

BACKGROUND Gestational diabetes affects almost 1 in 10 pregnancies and is associated with adverse outcomes including fetal demise. Pregnancy complications related to diabetes are attributed to placental vascular dysfunction. With diabetes, maternal hyperglycemia is thought to promote placental vasoconstriction. However, it remains poorly understood if and how hyperglycemia leads to placental vascular dysfunction or if humoral factors related to maternal diabetes are responsible. METHODS AND RESULTS Utilizing a human placenta dual cotyledon, dual perfusion assay we examined the arterial pressure response to the thromboxane mimetic U44619, in cotyledons exposed to normal vs. a hyperglycemic infusion into the intervillous space. Tissues were then analyzed for the activity of key signaling molecules related to vascular tone; eNOS, Akt, PKA and VEGFR2. Results indicate a significant increase in fetal vascular resistance with maternal exposure to hyperglycemia. This response corresponded with a reduction in the phosphorylation of eNOS at Ser1177 and Akt at Thr308. In contrast, VEGFR2 at Tyr1175 and PKA at Thr197 were not different with hyperglycemia. CONCLUSION Reductions of eNOS and Akt phosphorylation at key residues implicated in nitric oxide production suggest that hyperglycemia alters the vasodilatory signaling of placental vessels. In contrast, acute hyperglycemic exposure may not alter vasoconstriction via VEGF and PKA signaling. Altogether our results link hyperglycemic exposure in human placentas to nitric oxide signaling; a mechanisms that may account for the elevations in vascular resistance commonly observed in diabetic pregnancies.