title: Targeted gene delivery of BMPR2 attenuates pulmonary hypertension.
abstract: Pulmonary arterial hypertension (PAH) remains a fatal disease despite modern pharmacotherapy. Mutations in the gene for bone morphogenetic protein receptor type II (BMPR2) lead to reduced BMPR2 expression, which is causally linked to PAH. BMPR2 is predominantly expressed on pulmonary endothelium and has complex interactions with transforming growth factor (TGF)-β signalling mechanisms. Our objectives were to assess the effect on PAH of upregulating BMPR2 by targeted adenoviral BMPR2 gene delivery to the pulmonary vascular endothelium. We used two established rat models of PAH: chronic hypoxia and monocrotaline (MCT). In both hypertensive models, those receiving BMPR2 had less right ventricular hypertrophy, less pulmonary vascular resistance, improved cardiac function and reduced vascular remodelling. In the MCT model, there was an increase in TGF-β, which was prevented by BMPR2 treatment. In vitro, TGF-β1-induced endothelial-mesenchymal transition (EndMT) in human pulmonary microvascular endothelial cells, which was associated with reduced BMPR2 expression. EndMT was partially ameliorated by stimulating BMPR2 signalling with appropriate ligands even in the ongoing presence of TGF-β1. Collectively, these results indicate therapeutic potential for upregulation of the BMPR2 axis in PAH, which may be, in part, mediated by countering the remodelling effects of TGF-β.
authors: Dept of Thoracic Medicine Chest Clinic, Royal Adelaide Hospital, 275 North Terrace, Adelaide, SA 5000, Australia.
authors: A M
authors: AM
authors: Reynolds
authors: M D
authors: MD
authors: Holmes
authors: S M
authors: SM
authors: Danilov
authors: P N
authors: PN
authors: Reynolds
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics* / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D019076:Transgenes / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics
chemical_list: D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II