Abstract
Antenatal steroid treatment decreases morbidity and mortality in premature infants through the maturation of lung tissue, which enables sufficient breathing performance. However, clinical and animal studies have shown that repeated doses of glucocorticoids such as dexamethasone and betamethasone lead to long-term adverse effects on brain development. Therefore, we established a mouse model for antenatal dexamethasone treatment to investigate the effects of dexamethasone on brain vessel differentiation towards the blood-brain barrier (BBB) phenotype, focusing on molecular marker analysis. The major findings were that in total brains on postnatal day (PN) 4 triple antenatal dexamethasone treatment significantly downregulated the tight junction protein claudin-5, the endothelial marker Pecam-1/CD31, the glucocorticoid receptor, the NR1 subunit of the N-methyl-D-aspartate receptor, and Abc transporters (Abcb1a, Abcg2 Abcc4). Less pronounced effects were found after single antenatal dexamethasone treatment and in PN10 samples. Comparisons of total brain samples with isolated brain endothelial cells together with the stainings for Pecam-1/CD31 and claudin-5 led to the assumption that the morphology of brain vessels is affected by antenatal dexamethasone treatment at PN4. On the mRNA level markers for angiogenesis, the sonic hedgehog and the Wnt pathway were downregulated in PN4 samples, suggesting fundamental changes in brain vascularization and/or differentiation. In conclusion, we provided a first comprehensive molecular basis for the adverse effects of multiple antenatal dexamethasone treatment on brain vessel differentiation.
Highlights
The use of antenatal steroids to mature fetal lungs reduces neonatal morbidity and mortality in neonates born before 34 weeks of gestation [1,2]
It has been proposed that a disruption of the trophic coupling between brain endothelial cells and oligodendrocytes could lead to white matter dysfunction [7]
Triple maternal DEX treatment significantly reduced claudin-5 mRNA expression to 0.54 ± 0.04-fold (p
Summary
The use of antenatal steroids to mature fetal lungs reduces neonatal morbidity and mortality in neonates born before 34 weeks of gestation [1,2]. Animal studies have shown that exposure to repeated or high-dose antenatal glucocorticoids is associated with reduced fetal growth and long-term adverse effects on brain development, neuroendocrine function, blood pressure, and glucose homeostasis [5]. It has been proposed that a disruption of the trophic coupling between brain endothelial cells and oligodendrocytes could lead to white matter dysfunction [7] This hypothesis led us to investigate the effects of antenatal maternal dexamethasone treatment on the development of the bloodbrain barrier (BBB). Single maternal treatments with glucocorticoids, such as dexamethasone, led to the increased expression of tight junction proteins, such as claudin-5, in fetal sheep brains [11,12], but multiple dexamethasone treatment did not significantly regulate claudin-5. We established a mouse model to investigate the effects of single and multiple maternal antenatal dexamethasone treatments on key BBB molecules during development. In line with altered vessel morphology shown by immunofluoresence microscopy data revealed changes of key molecules of angiogenesis as well as genes of the sonic hedgehog (Shh) and the wingless int (Wnt) pathways on PN4
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