Mice expressing BMPR2R899X transgene in smooth muscle develop pulmonary vascular lesions
| Autor: | Daniel J. Crona, Brian Ickes, Kirk B. Lane, Karen A. Fagan, Sebastian Albu, Duncan J. Stewart, Yupu Deng, Julie W. Harral, James West |
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| Rok vydání: | 2008 |
| Předmět: |
Pulmonary and Respiratory Medicine
Pathology medicine.medical_specialty Systole Physiology Heart Ventricles Hypertension Pulmonary T-Lymphocytes Transgene Blood Pressure Smad Proteins Biology Bone Morphogenetic Protein Receptors Type II Bone morphogenetic protein p38 Mitogen-Activated Protein Kinases Mice Antigens CD Physiology (medical) medicine Animals Bone morphogenetic protein receptor AC133 Antigen Endothelium Transgenes Pulmonary pathology Phosphorylation Receptor Glycoproteins Mitogen-Activated Protein Kinase 1 Lung Neovascularization Pathologic Macrophages Cell Cycle Muscle Smooth Articles Cell Biology medicine.disease BMPR2 medicine.anatomical_structure Blood pressure Gene Expression Regulation Blood Vessels Leukocyte Common Antigens Mutant Proteins Peptides |
| Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology. 295:L744-L755 |
| ISSN: | 1522-1504 1040-0605 |
| DOI: | 10.1152/ajplung.90255.2008 |
| Popis: | Familial pulmonary arterial hypertension (PAH) is associated with mutations in bone morphogenetic protein type II receptor (BMPR2). Many of these mutations occur in the BMPR2 tail domain, leaving the SMAD functions intact. To determine the in vivo consequences of BMPR2 tail domain mutation, we created a smooth muscle-specific doxycycline-inducible BMPR2 mutation with an arginine to termination mutation at amino acid 899. When these SM22-rtTA x TetO7-BMPR2R899X mice had transgene induced for 9 wk, starting at 4 wk of age, they universally developed pulmonary vascular pruning as assessed by fluorescent microangiography. Approximately one-third of the time, the induced animals developed elevated right ventricular systolic pressures (RVSP), associated with extensive pruning, muscularization of small pulmonary vessels, and development of large structural pulmonary vascular changes. These lesions included large numbers of macrophages and T cells in their adventitial compartment as well as CD133-positive cells in the lumen. Small vessels filled with CD45-positive and sometimes CD3-positive cells were a common feature in all SM22-rtTA x TetO7-BMPR2R899X mice. Gene array experiments show changes in stress response, muscle organization and function, proliferation, and apoptosis and developmental pathways before RVSP increases. Our results show that the primary phenotypic result of BMPR2 tail domain mutation in smooth muscle is pulmonary vascular pruning leading to elevated RVSP, associated with early dysregulation in multiple pathways with clear relevance to PAH. This model should be useful to the research community in examining early molecular and physical events in the development of PAH and as a platform to validate potential treatments. |
| Databáze: | OpenAIRE |
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