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Hemodynamic Characterization of Rodent Models of Pulmonary Arterial Hypertension
Published on: April 11, 2016
Genotype-phenotype effects of Bmpr2 mutations on disease severity in mouse models of pulmonary hypertension
Andrea L Frump1, Arunima Datta2, Sampa Ghose2
1Department of Cell and Developmental Biology, Vanderbilt University, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Abstract:
More than 350 mutations in the type-2 BMP (bone morphogenetic protein) receptor, BMPR2, have been identified in patients with heritable pulmonary arterial hypertension (HPAH). However, only 30% of BMPR2 mutation carriers develop PAH, and we cannot predict which of these carriers will develop clinical disease. One possibility is that the nature of the BMPR2 mutation affects disease severity. This hypothesis has been difficult to test clinically, given the rarity of HPAH and the complexity of the confounding genetic and environmental risk factors. To test this hypothesis, therefore, we evaluated the susceptibility to experimental pulmonary hypertension (PH) of mice carrying different HPAH-associated Bmpr2 mutations on otherwise identical genetic backgrounds. Mice with Bmpr2ΔEx4-5 mutations (Bmpr2+/-), in which the mutant protein is not expressed, develop less severe PH in response to hypoxia or hypoxia with vascular endothelial growth factor receptor inhibition than mice with an extracellular-domain Bmpr2ΔEx2 mutation (Bmpr2ΔEx2/+), in which the mutant protein is expressed. This was associated with a marked decrease in stabilizing phosphorylation of threonine 495 endothelial nitric oxide synthase (pThr495 eNOS) in Bmpr2ΔEx2/+ compared to wild-type and Bmpr2+/- mouse lungs. These findings provide the first experimental evidence that BMPR2 mutation types influence the severity of HPAH and suggest that patients with BMPR2 mutations who express mutant BMPR2 proteins by escaping non-sense-mediated messenger RNA decay (NMD- mutations) will develop more severe disease than HPAH patients with NMD+ mutations who do not express BMPR2 mutant proteins. Since decreased levels of pThr495 eNOS are associated with increased eNOS uncoupling, our data also suggest that this effect may result from defects in eNOS function.
Insights
The type of bone morphogenetic protein receptor 2 (BMPR2) mutation influences heritable pulmonary arterial hypertension (HPAH) severity. Mutations leading to mutant BMPR2 protein expression result in more severe disease compared to those where the protein is not expressed.
Area of Science:
- Genetics and Molecular Biology
- Cardiovascular Research
- Pulmonary Medicine
Background:
- Over 350 mutations in BMPR2 are linked to heritable pulmonary arterial hypertension (HPAH).
- Only 30% of BMPR2 mutation carriers develop PAH, and disease severity is unpredictable.
- The specific nature of BMPR2 mutations may influence clinical disease development and severity.
Purpose of the Study:
- To investigate whether different types of BMPR2 mutations affect the severity of experimental pulmonary hypertension (PH).
- To determine if the expression of a mutant BMPR2 protein influences disease susceptibility and phenotype.
- To explore the role of endothelial nitric oxide synthase (eNOS) phosphorylation in BMPR2-associated PH.
Main Methods:
- Utilized mouse models with distinct HPAH-associated Bmpr2 mutations (Bmpr2ΔEx4-5 and Bmpr2ΔEx2) on identical genetic backgrounds.
- Assessed susceptibility to experimental PH induced by hypoxia or hypoxia with VEGF receptor inhibition.
- Measured the levels of phosphorylated threonine 495 endothelial nitric oxide synthase (pThr495 eNOS) in lung tissue.
Main Results:
- Mice with Bmpr2ΔEx4-5 mutations (no mutant protein expression) developed less severe PH compared to mice with Bmpr2ΔEx2 mutations (mutant protein expression).
- A significant decrease in pThr495 eNOS was observed in Bmpr2ΔEx2/+ mouse lungs compared to wild-type and Bmpr2ΔEx4-5/+ lungs.
- These findings suggest a correlation between mutant BMPR2 protein expression, reduced pThr495 eNOS, and increased PH severity.
Conclusions:
- Provides the first experimental evidence that BMPR2 mutation type impacts HPAH severity.
- Suggests that HPAH patients with BMPR2 mutations that escape nonsense-mediated decay (NMD-) and express mutant proteins may experience more severe disease.
- Hypothesizes that impaired eNOS function, potentially due to decreased pThr495 eNOS and increased eNOS uncoupling, contributes to disease pathogenesis.
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