title: Pulmonary hypertension in transgenic mice expressing a dominant-negative BMPRII gene in smooth muscle.
abstract: Bone morphogenetic peptides (BMPs), a family of cytokines critical to normal development, were recently implicated in the pathogenesis of familial pulmonary arterial hypertension. The type-II receptor (BMPRII) is required for recognition of all BMPs, and targeted deletion of BMPRII in mice results in fetal lethality before gastrulation. To overcome this limitation and study the role of BMP signaling in postnatal vascular disease, we constructed a smooth muscle-specific transgenic mouse expressing a dominant-negative BMPRII under control of the tetracycline gene switch (SM22-tet-BMPRII(delx4+) mice). When the mutation was activated after birth, mice developed increased pulmonary artery pressure, RV/LV+S ratio, and pulmonary arterial muscularization with no increase in systemic arterial pressure. Studies with SM22-tet-BMPRII(delx4+) mice support the hypothesis that loss of BMPRII signaling in smooth muscle is sufficient to produce the pulmonary hypertensive phenotype.
authors.affiliation: University of Colorado Health Sciences Center, Division of Pulmonary Sciences and Critical Care Medicine and Department of Anesthesia, Denver, Colo 80262, USA.
authors.forename: James
authors.initials: J
authors.lastname: West
authors.forename: Karen
authors.initials: K
authors.lastname: Fagan
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Steudel
authors.forename: Brian
authors.initials: B
authors.lastname: Fouty
authors.forename: Kirk
authors.initials: K
authors.lastname: Lane
authors.forename: Julie
authors.initials: J
authors.lastname: Harral
authors.forename: Marloes
authors.initials: M
authors.lastname: Hoedt-Miller
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tada
authors.forename: John
authors.initials: J
authors.lastname: Ozimek
authors.forename: Rubin
authors.initials: R
authors.lastname: Tuder
authors.forename: David M
authors.initials: DM
authors.lastname: Rodman
mesh_terms: D000818:Animals; D001794:Blood Pressure; D052006:Bone Morphogenetic Protein Receptors, Type II; D004318:Doxycycline / Q000494:pharmacology; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D011651:Pulmonary Artery / Q000503:physiopathology / Q000648:ultrastructure; D014162:Transfection; D019076:Transgenes
chemical_list: D017346:Protein Serine-Threonine Kinases; C498218:BMPR2 protein, human; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II; D004318:Doxycycline