Loss of BMPR2 Signaling in Smooth Muscle in Mouse Lung
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE5255 | GEO | 2006/07/08
SECONDARY ACCESSION(S): PRJNA96473
REPOSITORIES: GEO
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Project description:Familial pulmonary arterial hypertension (fPAH) is associated with mutations in BMPR2. Many of these mutations occur in the BMPR2 tail domain, leaving the SMAD functions intact. In order 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 weeks, starting at 4 weeks of age, they universally developed pulmonary vascular pruning as assessed by fluorescent microangiography. Approximately half 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. Keywords: Disease state analysis
2008-06-01 | GSE11018 | GEO
Project description:Familial pulmonary arterial hypertension (fPAH) is associated with mutations in BMPR2. Many of these mutations occur in the BMPR2 tail domain, leaving the SMAD functions intact. In order 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 weeks, starting at 4 weeks of age, they universally developed pulmonary vascular pruning as assessed by fluorescent microangiography. Approximately half 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. Experiment Overall Design: Each array is an individual female mouse, age-matched, with two mice & arrays used for each of controls (transactivator only), BMPR2-R899X with normal RVSP, and BMPR2-R899X with high RVSP.
2008-06-18 | E-GEOD-11018 | biostudies-arrayexpress
Project description:Mice expressing a doxycycline-inducible dominant negative BMPR2 transgene expressed only in smooth muscle are activated for one or eight weeks, and compared to transactivator-only mice also fed doxycycline. All mice are 12 weeks of old at sacrifice. Experiment Overall Design: Each chip is a pool of three individual mice, to reduce variability. The transactivator-only mice are controls. The other mice all had elevated RV pressures at time of sacrifice. RNA was prepared from whole lung.
2007-11-27 | E-GEOD-5255 | biostudies-arrayexpress
Project description:BMPR2 mutation causes pulmonary arterial hypertension (PAH); ACE2 treatment can resolve established BMPR2-mediated PAH. The purpose of this study was to uncover the molecular mechanism behind this. Four groups: +/- ACE2 and +/- BMPR2 transgene, two arrays each, each array a pool of three animals.
2010-08-24 | E-GEOD-21583 | biostudies-arrayexpress
Project description:Analysis of mammary glands from tet-inducible (rtTA) transgenic mice expressing cyclin D1 (Ccnd1). MMTV-rtTA transgenic mice (MMTV-Mouse Mammary Tumor Virus promoter) were cross-mated to cyclin D1 transgenic mice under the control of the tet operon. 8-week-old tetracycline-inducible cyclin D1/rtTA bi-transgenic pregnant female mice (12 days postcoitus) were treated with doxycycline through drinking water supplementation at a final concentration of 2 mg/ml. Control mice were rtTA transgenics alone and were treated in the same manner. After 7 days of doxycycline treatment, the mice were sacrificed and mammary glands taken for RNA isolation. Results provide insight into the in vivo gene expression pattern regulated by cyclin D1 through acute induction. Two separate control mice positive for the MMTV-rtTA transgene were compared to 3 separate cyclin D1/rtTA bi-transgenic female mice.
2012-02-10 | E-GEOD-35076 | biostudies-arrayexpress
Project description:Effect of induction of MMP3 expression in CCSP-rtTA/tet-MMP3 transgenic mice, fed doxycycline for 14 weeks We used microarrays to detail the global programme of gene expression following MMP3 expression
2010-11-18 | GSE25439 | GEO
Project description:Pulmonary arterial hypertension (PAH) is thought to be driven by dysfunction of pulmonary vascular microendothelial cells (PMVEC). Most hereditary PAH is associated with BMPR2 mutations. However, the physiologic and molecular consequences of expression of BMPR2 mutations in PMVEC are unknown. PMVEC were isolated from triple transgenic mice carrying the immortomouse gene, a transactivator, and either control, Bmpr2delx4+ or Bmpr2R899X mutation
2011-07-01 | E-GEOD-28043 | biostudies-arrayexpress
Project description:P190B RhoGAP is required for mammary gland development, and its overexpression disrupts mammary gland branching morphogenesis. To better understand the mechanisms by which p190B regulates mammary gland development we performed gene expression microarray analysis on mammary epithelial cells isolated from p190B overexpressing transgenic mice compared to control mice. The mice used in this study were previously developed to inducibly overexpress p190B selectively in the mammary gland (Vargo-Gogola 2006). FVB/N mice carrying the MMTV-rtTA and TetO-p190B-IRES-luciferase transgenes or the MMTV-rtTA transgene only (Gunther EJ, FASEB) were fed doxycycline (Dox) chow (2 g/kg) for 7 d prior to removal of mammary glands and isolation of primary mammary epithelial cells at 6 weeks of age.
2011-01-22 | E-GEOD-26771 | biostudies-arrayexpress
Project description:Purpose: The goal of this study was to characterize the atrial and ventricular transcriptomic changes in a cardiac mouse model of myotonic dystrophy. The mouse model utilizes a bitransgenic system for doxycycline (dox) inducible and cardiomyocyte specific expression of pathogenic RNA containing 960 CUG repeats. Bitransgenic animals (called CUG960 mice) homozygous for the TREDT960I transgene (containing 960 interrupted CTG repeats) and hemizygous for reverse transactivator (rtTA) transgene containing a cardiomyocyte-specific alpha myosin heavy chain promoter are given dox food for expression of CUG repeat RNA. Mice hemizygous for rtTA transgene (MHCrtTA) given dox food were used as controls. Methods:We performed RNA-seq for high-resolution analysis of transcriptomic alterations in atria and ventricles of CUG960 experimental and MHCrtTA control mice given dox chow since postnatal day 1 (PN1) for a period of 10 weeks. Results: We identified pathogenic CUG repeat RNA induced gene expression and alternative splicing changes in ion transport genes that are associated with inherited cardiac conduction diseases, including a subset of genes involved in calcium handling. Conclusions: We identified potential tissue-specific mechanisms contributing to the cardiac disease relevant phenotypes in an animal model of DM1.
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