title: Chronic allergic inflammation causes vascular remodeling and pulmonary hypertension in BMPR2 hypomorph and wild-type mice.
abstract: Loss-of-function mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene have been identified in patients with heritable pulmonary arterial hypertension (PAH); however, disease penetrance is low, suggesting additional factors play a role. Inflammation is associated with PAH and vascular remodeling, but whether allergic inflammation triggers vascular remodeling in individuals with BMPR2 mutations is unknown. Our goal was to determine if chronic allergic inflammation would induce more severe vascular remodeling and PAH in mice with reduced BMPR-II signaling. Groups of Bmpr2 hypomorph and wild-type (WT) Balb/c/Byj mice were exposed to house dust mite (HDM) allergen, intranasally for 7 or 20 weeks to generate a model of chronic inflammation. HDM exposure induced similar inflammatory cell counts in all groups compared to controls. Muscularization of pulmonary arterioles and arterial wall thickness were increased after 7 weeks HDM, more severe at 20 weeks, but similar in both groups. Right ventricular systolic pressure (RVSP) was measured by direct cardiac catheterization to assess PAH. RVSP was similarly increased in both HDM exposed groups after 20 weeks compared to controls, but not after 7 weeks. Airway hyperreactivity (AHR) to methacholine was also assessed and interestingly, at 20 weeks, was more severe in HDM exposed Bmpr2 hypomorph mice versus WT. We conclude that chronic allergic inflammation caused PAH and while the severity was mild and similar between WT and Bmpr2 hypomorph mice, AHR was enhanced with reduced BMPR-II signaling. These data suggest that vascular remodeling and PAH resulting from chronic allergic inflammation occurs independently of BMPR-II pathway alterations.
authors.affiliation: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Mushaben
authors.forename: Gurjit Khurana
authors.initials: GK
authors.lastname: Hershey
authors.forename: Michael W
authors.initials: MW
authors.lastname: Pauciulo
authors.forename: William C
authors.initials: WC
authors.lastname: Nichols
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Le Cras
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001160:Arterioles / Q000473:pathology; D001794:Blood Pressure; D015153:Blotting, Western; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D018893:Bronchoalveolar Lavage; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005838:Genotype; D006967:Hypersensitivity / Q000150:complications*; D006976:Hypertension, Pulmonary / Q000209:etiology*; D007150:Immunohistochemistry; D007249:Inflammation / Q000150:complications*; D016210:Methacholine Chloride; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D039981:Pyroglyphidae; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D017931:DNA Primers; D016210:Methacholine Chloride; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II