Abstract
BackgroundPulmonary hypertension (PH) is a lethal disease that is associated with characteristic histological abnormalities of the lung vasculature and defects of angiopoetin-1 (ANG-1), TIE-2 and bone morphogenetic protein receptor (BMPR)-related signalling. We hypothesized that if these signalling defects cause PH generically, they will be readily identifiable perinatally in congenital diaphragmatic hernia (CDH), where the typical pulmonary vascular changes are present before birth and are accompanied by PH after birth.MethodsCDH (predominantly left-sided, LCDH) was created in Sprague-Dawley rat pups by e9.5 maternal nitrofen administration. Left lungs from normal and LCDH pups were compared at fetal and postnatal time points for ANG-1, TIE-2, phosphorylated-TIE-2, phosphorylated-SMAD1/5/8 and phosphorylated-ERK1/2 by immunoprecipitation and Western blotting of lung protein extracts and by immunohistochemistry on lung sections.ResultsIn normal lung, pulmonary ANG-1 protein levels fall between fetal and postnatal life, while TIE-2 levels increase. Over the corresponding time period, LCDH lung retained normal expression of ANG-1, TIE-2, phosphorylated-TIE-2 and, downstream of BMPR, phosphorylated-SMAD1/5/8 and phosphorylated-p44/42.ConclusionIn PH and CDH defects of ANG-1/TIE-2/BMPR-related signalling are not essential for the lethal vasculopathy.
Highlights
Pulmonary arterial hypertension (PH) remains a lethal disease: understanding its pathogenesis is a key priority in the search for effective therapies
To test if increased ANG-1/TIE-2 activity suppresses bone morphogenetic protein receptor (BMPR) signalling to generate Pulmonary hypertension (PH) as postulated in human adult studies, we first tested if ANG-1/TIE-2 activity was abnormally increased in the perinatal congenital diaphragmatic hernia (CDH) lung with its established pulmonary vascular changes typical of PH
There was no significant difference between the level of ANG-1 protein between control and left CDH (LCDH) lung (Figure 2b)
Summary
Pulmonary arterial hypertension (PH) remains a lethal disease: understanding its pathogenesis is a key priority in the search for effective therapies. Even in non-familial PAH, altered BMPR-2 signalling may result from reduced pulmonary expression of BMPR-1A (with which BMPR-2 normally heterodimerizes for function) [4]. Reduced BMPR-1A expression is induced in vitro by vascular growth factor, angiopoetin-1 (ANG-1) signalling through TIE-2; elevations in both of these are strongly correlated with disease severity in nonfamilial PAH lung [4]. Pulmonary hypertension (PH) is a lethal disease that is associated with characteristic histological abnormalities of the lung vasculature and defects of angiopoetin-1 (ANG-1), TIE-2 and bone morphogenetic protein receptor (BMPR)related signalling. We hypothesized that if these signalling defects cause PH generically, they will be readily identifiable perinatally in congenital diaphragmatic hernia (CDH), where the typical pulmonary vascular changes are present before birth and are accompanied by PH after birth
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