Effect of maternal administration of betamethasone on peripheral arterial development in fetal rabbit lungs.
OBJECTIVE
Glucocorticoids promote lung maturation and reduce the incidence of respiratory distress syndrome in premature newborns. We hypothesized that betamethasone (BM), which is known to induce thinning of the alveolar walls, would also thin the arterial media and adventitia of intra-parenchymatic vessels in developing rabbit lungs.


METHODS
112 fetuses from 21 time-mated, pregnant, giant white rabbits received maternal injections of BM at either 0.05 or 0.1 mg/kg/day on days 25-26 of gestational age. Controls received either saline (10 does, 56 fetuses) or no injection (10 does, 59 fetuses). Fetuses were harvested from day 27 onwards until term (day 31). 44 additional fetuses (8 does) were harvested between days 23 and 26. Endpoints were wet lung-to-body weight ratio, vascular morphometric indices and immunohistochemistry staining for alpha-smooth muscle actin, Flk-1, vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS). ANOVA (Tukey's test) and independent t test (p < 0.05) were used for comparison between BM and saline groups.


RESULTS
Maternal BM injected on days 25-26 to pregnant rabbits induced a significant decrease in fetal body and lung weight and the lung-to-body weight ratio in the preterm pups shortly after injection. BM led to a dose-dependent thinning of the arterial media and adventitia (pulmonary arteries with an external diameter (ED) of <100 microm), to an increase in the percentage of non-muscularized peripheral vessels (ED <60 microm), in eNOS and VEGF immunoreactivity of the endothelial and smooth muscle cells in the pulmonary vessels and to an increase in Flk-1-positive pulmonary epithelial cell density.


CONCLUSIONS
Maternal administration of BM caused thinning of the arterial wall of pulmonary vessels (ED <100 microm) and a decrease in muscularization in peripheral vessels (ED <60 microm). This coincided with increased expression of Flk-1 in the endothelium and smooth muscle cells of the pulmonary arteries. All the effects studied were dose-dependent.
Roubliova
Xenia I
XI
Center for Surgical Technologies, Faculty of Medicine, Katholieke Universiteit Leuven Leuven, Belgium.
Van der Biest
Anne-Marie
AM
Vaast
Pascal
P
Lu
HuiQi
H
Jani
Jacques C
JC
Lewi
Paul J
PJ
Verbeken
Eric K
EK
Tibboel
Dick
D
Deprest
Jan A
JA
D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000196:embryology*; D001623:Betamethasone / Q000494:pharmacology*; D005260:Female; D047109:Fetal Development / Q000187:drug effects; D005865:Gestational Age; D005938:Glucocorticoids / Q000494:pharmacology*; D008168:Lung / Q000098:blood supply* / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000196:embryology; D011247:Pregnancy; D011817:Rabbits; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D005938:Glucocorticoids; D001623:Betamethasone; D040301:Vascular Endothelial Growth Factor Receptor-2