Abstract
Background: Pulmonary hypertension is the major cause of morbidity and mortality in congenital diaphragmatic hernia (CDH). Mutations in several genes that encode signaling molecules of the transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) pathways have previously been associated with CDH. Since studies on the activation of these pathways in CDH are scarce, and have yielded inconsistent conclusions, the downstream activity of both pathways was assessed in the nitrofen-CDH rat model.Methods and Results: Pregnant Sprague-Dawley rats were treated with nitrofen at embryonic day (E) 9.5 to induce CDH in offspring. At E21, lungs were screened for the expression of key factors of both signaling pathways, at both the mRNA transcript and protein levels. Subsequently, paying particular attention to the pulmonary vasculature, increased phosphorylation of SMAD2, and decreased phosphorylation of Smad5 was noted in the muscular walls of small pulmonary vessels, by immunohistochemistry. This was accompanied by increased proliferation of constituent cells of the smooth muscle layer of these vessels.Conclusions: Increased activation of the TGFβ pathway and decreased activation of the BMP pathway in the pulmonary vasculature of rats with experimentally-induced CDH, suggesting that the deregulated of these important signaling pathways may underlie the development of pulmonary hypertension in CDH.
Highlights
Congenital diaphragmatic hernia (CDH) is a severe developmental anomaly characterized by a diaphragmatic defect
The degree of phosphorylation of SMAD2 was not different in whole lung homogenates of CDH pups compared to controls (Figure 2C)
Since the abnormalities in the pulmonary vasculature are key pathological hallmarks of CDH, changes in SMAD phosphorylation were assessed in the small pulmonary vessels (25–50 μm) using immunofluorescence staining
Summary
Congenital diaphragmatic hernia (CDH) is a severe developmental anomaly characterized by a diaphragmatic defect. TGFb and BMP in CDH growth factor β (TGFβ) and bone morphogenetic protein (BMP) pathways have been described in both adult and pediatric patients with familial, heritable, and idiopathic pulmonary arterial hypertension (PAH). Of these genes, the BMP receptor 2 (BMPR2) is most commonly affected [2]. TGFβ signaling is active in the vascular and airway smooth muscle and alveolar and airway epithelium during late lung development Both up- and downregulation of TGFβ signaling impairs the alveolarization process [3, 4], depending on the period of study during gestation. Since studies on the activation of these pathways in CDH are scarce, and have yielded inconsistent conclusions, the downstream activity of both pathways was assessed in the nitrofen-CDH rat model
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