Multiple Antenatal Dexamethasone Treatment Alters Brain Vessel Differentiation in Newborn Mouse Pups.
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.
Department of Anaesthesia and Critical Care, University of Wuerzburg, Wuerzburg, Germany; Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria; Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.
Winfried
W
Neuhaus
Department of Anaesthesia and Critical Care, University of Wuerzburg, Wuerzburg, Germany.
Marian
M
Schlundt
University Children's Hospital Wuerzburg, Wuerzburg, Germany.
Markus
M
Fehrholz
Institute of Neurology (Edinger Institute), Johann Wolfgang Goethe University, Frankfurt, Germany.
Alexander
A
Ehrke
University Children's Hospital Wuerzburg, Wuerzburg, Germany.
Steffen
S
Kunzmann
Institute of Neurology (Edinger Institute), Johann Wolfgang Goethe University, Frankfurt, Germany.
Stefan
S
Liebner
University Children's Hospital Wuerzburg, Wuerzburg, Germany.
Christian P
CP
Speer
Department of Anaesthesia and Critical Care, University of Wuerzburg, Wuerzburg, Germany.
Carola Y
CY
Förster
D000818:Animals; D000831:Animals, Newborn; D000943:Antigens, Differentiation / Q000096:biosynthesis*; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D002561:Cerebrovascular Disorders / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D003907:Dexamethasone / Q000009:adverse effects* / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D060449:Wnt Signaling Pathway / Q000187:drug effects*
D000943:Antigens, Differentiation; D003907:Dexamethasone