title: Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension.
abstract: Mutations in the bone morphogenetic protein type II receptor gene (BMPR2) are the major genetic cause of familial pulmonary arterial hypertension (FPAH). Although smooth muscle cell proliferation contributes to the vascular remodeling observed in PAH, the role of BMPs in this process and the impact of BMPR2 mutation remains unclear. Studies involving normal human pulmonary artery smooth muscle cells (PASMCs) suggest site-specific responses to BMPs. Thus, BMP-4 inhibited proliferation of PASMCs isolated from proximal pulmonary arteries, but stimulated proliferation of PASMCs from peripheral arteries, and conferred protection from apoptosis. These differences were not caused by differential activation of BMP signaling pathways because exogenous BMP-4 led to phosphorylation of Smad1, p38(MAPK), and ERK1/2 in both cell types. However, the proproliferative effect of BMP-4 on peripheral PASMCs was found to be p38MAPK/ERK-dependent. Conversely, overexpression of dominant-negative Smad1 converted the response to BMP-4 in proximal PASMCs from inhibitory to proliferative. Furthermore, we confirmed that proximal PASMCs harboring kinase domain mutations in BMPR2 are deficient in Smad signaling and are unresponsive to the growth suppressive effect of BMP-4. Moreover, we show that the pulmonary vasculature of patients with familial and idiopathic PAH are deficient in the activated form of Smad1. We conclude that defective Smad signaling and unopposed p38(MAPK)/ERK signaling, as a consequence of mutation in BMPR2, underlie the abnormal vascular cell proliferation observed in familial PAH.
authors.affiliation: Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Xudong
authors.initials: X
authors.lastname: Yang
authors.forename: Lu
authors.initials: L
authors.lastname: Long
authors.forename: Mark
authors.initials: M
authors.lastname: Southwood
authors.forename: Nung
authors.initials: N
authors.lastname: Rudarakanchana
authors.forename: Paul D
authors.initials: PD
authors.lastname: Upton
authors.forename: Trina K
authors.initials: TK
authors.lastname: Jeffery
authors.forename: Carl
authors.initials: C
authors.lastname: Atkinson
authors.forename: Hailan
authors.initials: H
authors.lastname: Chen
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D055415:Bone Morphogenetic Protein 4; D052006:Bone Morphogenetic Protein Receptors, Type II; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000473:pathology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins; D051898:Smad1 Protein; D015534:Trans-Activators / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; C497399:SMAD1 protein, human; D051785:Smad Proteins; D051898:Smad1 Protein; D015534:Trans-Activators; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II