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Induction and Characterization of Pulmonary Hypertension in Mice using the Hypoxia/SU5416 Model
Published on: June 3, 2020
Defective pulmonary vascular remodeling in Smad8 mutant mice
Zheng Huang1, Degang Wang, Kaori Ihida-Stansbury
1Institute of Biosciences and Technology, Texas A&M System Health Science Center, 2121 W. Holcombe Blvd, Houston, TX 77030, USA.
Human Molecular Genetics
|May 8, 2009
Summary
Smad8 gene loss in adult mice caused pulmonary hypertension and lung tumors, suggesting its role in these diseases. This finding implicates Smad8 as a potential candidate gene for human pulmonary artery hypertension.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Genetics
Background:
- Pulmonary artery hypertension (PAH) is a severe condition leading to right heart failure.
- Bone morphogenetic protein (Bmp) signaling, particularly BmpRII mutations, is linked to PAH pathogenesis.
- Downstream effectors of BmpRII in PAH remain incompletely understood.
Purpose of the Study:
- To investigate the function of Smad8, a downstream mediator of Bmp-signaling, in pulmonary hypertension.
- To determine Smad8's role in pulmonary arterial remodeling and lung tumorigenesis.
Main Methods:
- Gene targeting in mice to create Smad8 loss-of-function models.
- Analysis of pulmonary vasculature for pathologic changes.
- Assessment of signaling pathways, including Activin/Tgfbeta.
- Evaluation of gene expression, including Prx1 and Tenascin-C.
- Monitoring for tumor development in Smad8 mutant mice.
Main Results:
- Adult Smad8 loss-of-function mice exhibited pulmonary artery medial thickening and smooth muscle hyperplasia, mirroring human PAH.
- Smad8 mutant pulmonary vasculature showed increased Activin/Tgfbeta signaling and aberrant Prx1 and Tenascin-C expression.
- A subset of Smad8 mutants developed pulmonary adenomas, indicating a role in growth control.
Conclusions:
- Smad8 plays a critical role in maintaining pulmonary vascular health and regulating lung growth.
- Smad8 deficiency contributes to the development of pulmonary hypertension and lung tumors.
- Smad8 is a potential candidate gene for human pulmonary artery hypertension.
