title: Mice expressing BMPR2R899X transgene in smooth muscle develop pulmonary vascular lesions.
abstract: 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 TetO(7)-BMPR2(R899X) 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 TetO(7)-BMPR2(R899X) 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.
authors: Vanderbilt University, 1161 21st Avenue S., Nashville, TN 37232-2650, USA. j.west@vanderbilt.edu
authors: James
authors: J
authors: West
authors: Julie
authors: J
authors: Harral
authors: Kirk
authors: K
authors: Lane
authors: Yupu
authors: Y
authors: Deng
authors: Brian
authors: B
authors: Ickes
authors: Daniel
authors: D
authors: Crona
authors: Sebastian
authors: S
authors: Albu
authors: Duncan
authors: D
authors: Stewart
authors: Karen
authors: K
authors: Fagan
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001794:Blood Pressure; D001808:Blood Vessels / Q000378:metabolism / Q000503:physiopathology; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D002453:Cell Cycle; D004727:Endothelium / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000378:metabolism; D006352:Heart Ventricles / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008264:Macrophages / Q000166:cytology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009130:Muscle, Smooth / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D050505:Mutant Proteins / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation; D051785:Smad Proteins / Q000378:metabolism; D013599:Systole; D013601:T-Lymphocytes / Q000166:cytology; D019076:Transgenes / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; D050505:Mutant Proteins; D010455:Peptides; C000606024:Prom1 protein, mouse; D051785:Smad Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048051:p38 Mitogen-Activated Protein Kinases; D052006:Bone Morphogenetic Protein Receptors, Type II; D017493:Leukocyte Common Antigens