The Role of Activin Receptor-Like Kinase 1 Signaling in the Pulmonary Vasculature of Experimental Diaphragmatic Hernia

Hofmann, Alejandro D.; Zimmer, Julia; Takahashi, Toshiaki; Gosemann, Jan‐Hendrik; Puri, Prem

doi:10.1055/s-0035-1566105

Cited by 3 publications

(1 citation statement)

References 36 publications

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“…104 In nitrofen CDH lungs, expression of ALK-1 is upregulated at E21 in the pulmonary vasculature. 127 The expression of TGF-β1 has been reported as increased in PASMCs of newborn pups with CDH compared with those of controls. 128 Elastin microfibril interfacelocated protein 1 (Emilin-1), expressed by PASMCs, is essential for elastogenesis and inhibits TGF-β signaling by binding to its precursor.…”

Section: Endothelial Cells Converts Ppet-1 Into Active Et-1mentioning

confidence: 99%

Pulmonary hypertension secondary to congenital diaphragmatic hernia: factors and pathways involved in pulmonary vascular remodeling

2019

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Congenital diaphragmatic hernia (CDH) is a severe birth defect that is characterized by pulmonary hypoplasia and pulmonary hypertension (PHTN). PHTN secondary to CDH is a result of vascular remodeling, a structural alteration in the pulmonary vessel wall that occurs in the fetus. Factors involved in vascular remodeling have been reported in several studies, but their interactions remain unclear. To help understand PHTN pathophysiology and design novel preventative and treatment strategies, we have conducted a systematic review of the literature and comprehensively analyzed all factors and pathways involved in the pathogenesis of pulmonary vascular remodeling secondary to CDH in the nitrofen model. Moreover, we have linked the dysregulated factors with pathways involved in human CDH. Of the 358 full-text articles screened, 75 studies reported factors that play a critical role in vascular remodeling secondary to CDH. Overall, the impairment of epithelial homeostasis present in pulmonary hypoplasia results in altered signaling to endothelial cells, leading to endothelial dysfunction. This causes an impairment of the crosstalk between endothelial cells and pulmonary artery smooth muscle cells, resulting in increased smooth muscle cell proliferation, resistance to apoptosis, and vasoconstriction, which clinically translate into PHTN.

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Section: Endothelial Cells Converts Ppet-1 Into Active Et-1mentioning

confidence: 99%

Pulmonary hypertension secondary to congenital diaphragmatic hernia: factors and pathways involved in pulmonary vascular remodeling

2019

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Decreased Endoglin expression in the pulmonary vasculature of nitrofen-induced congenital diaphragmatic hernia rat model

et al. 2016

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

et al. 2021

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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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The Role of Activin Receptor-Like Kinase 1 Signaling in the Pulmonary Vasculature of Experimental Diaphragmatic Hernia

Abstract: Upregulated gene and increased protein expression of ALK-1 in the pulmonary vasculature of nitrofen-induced CDH suggest that increased expression of ALK-1 may play a crucial role in the molecular pathogenesis of vascular remodeling induced PH in experimental CDH.

Cited by 3 publications

References 36 publications

Pulmonary hypertension secondary to congenital diaphragmatic hernia: factors and pathways involved in pulmonary vascular remodeling

Pulmonary hypertension secondary to congenital diaphragmatic hernia: factors and pathways involved in pulmonary vascular remodeling

Decreased Endoglin expression in the pulmonary vasculature of nitrofen-induced congenital diaphragmatic hernia rat model

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

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