Related Experiment Video
Updated: Jul 6, 2026
Establishment and Validation of a Rat Model of Pulmonary Arterial Hypertension Associated with Pulmonary Fibrosis
Published on: May 23, 2025
Smad signaling in the rat model of monocrotaline pulmonary hypertension
Margaret F Ramos1, Michael W Lamé, Henry J Segall
1Department of Pathology, , University of California, Davis, Davis, California, USA.
Abstract:
Mutations in the bone morphogenetic protein receptor type II (BMPrII) gene have been implicated in the development of familial pulmonary artery hypertension (PAH). The function of BMP signal transduction within the pulmonary vasculature and the role BMPrII mutations have in the development of PAH are incompletely understood. We used the monocrotaline (MCT) model of PAH to examine alterations in Smad signal transduction pathways in vivo. Lungs harvested from Sprague-Dawley rats treated with a single 60-mg/kg intraperitoneal (IP) injection of MCT were compared to saline-treated controls 2 weeks following treatment. Smad 4 was localized by immunohistochemistry to endothelial nuclei of the intra-acinar vessels undergoing remodeling. Smad 4, common to both BMP and transforming growth factor beta (TGFbeta) signaling, and BMP-specific Smad 1 were significantly decreased in western blot from whole lungs of treated animals, while no change was found for TGFbeta-specific Smad 2. MCT-treated rats also had increased expression of phosphorylated Smad 1 (P-Smad 1) but not phosphorylated Smad 2 (P-Smad 2). There was a decrease in the expression of the full BMPrII protein but not its short form variant in MCT-treated rat lungs. The type I receptor Alk1 had increased expression. Collectively, our data indicate that vascular remodeling in the MCT model is associated with alterations in BMP receptors and persistent endothelial Smad 1 signaling.
Insights
Pulmonary artery hypertension (PAH) involves bone morphogenetic protein receptor type II (BMPrII) gene mutations. This study reveals altered BMP signaling pathways and receptor expression in a rat model, offering insights into PAH development.
Area of Science:
- Molecular Biology
- Cardiovascular Research
- Pulmonary Hypertension
Background:
- Mutations in bone morphogenetic protein receptor type II (BMPrII) are linked to familial pulmonary artery hypertension (PAH).
- The precise role of BMP signal transduction and BMPrII mutations in PAH pathogenesis remains unclear.
- Understanding these pathways is crucial for developing effective PAH treatments.
Purpose of the Study:
- To investigate alterations in Smad signal transduction pathways in the monocrotaline (MCT)-induced rat model of PAH.
- To examine the expression of BMP receptors and Smad proteins in pulmonary vascular remodeling.
- To elucidate the functional consequences of BMPrII mutations in PAH development.
Main Methods:
- Utilized the monocrotaline (MCT) model of pulmonary artery hypertension (PAH) in Sprague-Dawley rats.
- Analyzed lung tissue 2 weeks post-MCT or saline treatment using immunohistochemistry and Western blotting.
- Assessed the expression and localization of Smad proteins (Smad 1, Smad 2, Smad 4) and BMP receptors (BMPrII, Alk1).
Main Results:
- Smad 4 localized to endothelial nuclei in remodeled intra-acinar vessels.
- Decreased expression of full-length BMPrII and Smad 1, with increased phosphorylated Smad 1 (P-Smad 1) and Alk1.
- No significant changes in Smad 2 or phosphorylated Smad 2 (P-Smad 2) expression were observed.
Conclusions:
- Vascular remodeling in the MCT-induced PAH model is associated with significant alterations in BMP receptor expression.
- Persistent endothelial Smad 1 signaling, despite decreased Smad 1 levels, suggests a complex regulatory mechanism in PAH.
- These findings highlight the critical role of BMP signaling in the pathophysiology of pulmonary artery hypertension.
