title: Dosage-dependent requirement of BMP type II receptor for maintenance of vascular integrity.
abstract: Germ-line mutations in bone morphogenic protein type II receptor (Bmpr2) confer susceptibility to pulmonary arterial hypertension (PAH), which is characterized by obstructive vascular lesions in small arteries. The molecular and cellular mechanisms that account for the etiology of this disorder remain elusive, as does the role of Bmpr2 in postnatal tissue homeostasis. Here we show that in adult mice, stably silencing Bmpr2 expression by RNA interference does not increase pulmonary arterial resistance but results in severe mucosal hemorrhage, incomplete mural cell coverage on vessel walls, and gastrointestinal hyperplasia. We present evidence that BMP receptor signaling regulates vascular remodeling during angiogenesis by maintaining the expression of endothelial guidance molecules that promote vessel patterning and maturation and by counteracting growth factor-induced AKT activation. Attenuation of this function may cause vascular dysmorphogenesis and predisposition to angioproliferative diseases. Our findings provide a mechanistic link between PAH and other diseases associated with the BMP/TGF-beta pathways, such as hereditary hemorrhagic telangiectasia and juvenile polyposis syndrome.
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. dong.liu@novartis.com
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Bernd
authors.initials: B
authors.lastname: Kinzel
authors.forename: Matthias
authors.initials: M
authors.lastname: Müeller
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Mao
authors.forename: Reginald
authors.initials: R
authors.lastname: Valdez
authors.forename: Yongxing
authors.initials: Y
authors.lastname: Liu
authors.forename: En
authors.initials: E
authors.lastname: Li
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D018628:Gene Dosage; D018095:Germ-Line Mutation; D006470:Hemorrhage / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D051057:Proto-Oncogene Proteins c-akt; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II