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Opposing Effects of TGFβ and BMP in the Pulmonary Vasculature in Congenital Diaphragmatic Hernia

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 associat...

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Autores principales: Mous, Daphne S., Buscop-van Kempen, Marjon J., Wijnen, Rene M. H., Tibboel, Dick, Morty, Rory E., Rottier, Robbert J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991367/
https://www.ncbi.nlm.nih.gov/pubmed/33777983
http://dx.doi.org/10.3389/fmed.2021.642577
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author Mous, Daphne S.
Buscop-van Kempen, Marjon J.
Wijnen, Rene M. H.
Tibboel, Dick
Morty, Rory E.
Rottier, Robbert J.
author_facet Mous, Daphne S.
Buscop-van Kempen, Marjon J.
Wijnen, Rene M. H.
Tibboel, Dick
Morty, Rory E.
Rottier, Robbert J.
author_sort Mous, Daphne S.
collection PubMed
description 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.
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spelling pubmed-79913672021-03-26 Opposing Effects of TGFβ and BMP in the Pulmonary Vasculature in Congenital Diaphragmatic Hernia Mous, Daphne S. Buscop-van Kempen, Marjon J. Wijnen, Rene M. H. Tibboel, Dick Morty, Rory E. Rottier, Robbert J. Front Med (Lausanne) Medicine 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. Frontiers Media S.A. 2021-03-11 /pmc/articles/PMC7991367/ /pubmed/33777983 http://dx.doi.org/10.3389/fmed.2021.642577 Text en Copyright © 2021 Mous, Buscop-van Kempen, Wijnen, Tibboel, Morty and Rottier. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Medicine
Mous, Daphne S.
Buscop-van Kempen, Marjon J.
Wijnen, Rene M. H.
Tibboel, Dick
Morty, Rory E.
Rottier, Robbert J.
Opposing Effects of TGFβ and BMP in the Pulmonary Vasculature in Congenital Diaphragmatic Hernia
title Opposing Effects of TGFβ and BMP in the Pulmonary Vasculature in Congenital Diaphragmatic Hernia
title_full Opposing Effects of TGFβ and BMP in the Pulmonary Vasculature in Congenital Diaphragmatic Hernia
title_fullStr Opposing Effects of TGFβ and BMP in the Pulmonary Vasculature in Congenital Diaphragmatic Hernia
title_full_unstemmed Opposing Effects of TGFβ and BMP in the Pulmonary Vasculature in Congenital Diaphragmatic Hernia
title_short Opposing Effects of TGFβ and BMP in the Pulmonary Vasculature in Congenital Diaphragmatic Hernia
title_sort opposing effects of tgfβ and bmp in the pulmonary vasculature in congenital diaphragmatic hernia
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991367/
https://www.ncbi.nlm.nih.gov/pubmed/33777983
http://dx.doi.org/10.3389/fmed.2021.642577
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