title: Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor.
abstract: BACKGROUND
  Mutations in the type II receptor for bone morphogenetic protein (BMPR-II), a receptor member of the transforming growth factor-beta (TGF-beta) superfamily, underlie many familial and sporadic cases of primary pulmonary hypertension (PPH).
  
  
  RESULTS
  Because the sites of expression of BMPR-II in the normal and hypertensive lung are unknown, we studied the cellular localization of BMPR-II and the related type I and II receptors for TGF-beta by immunohistochemistry in lung sections from patients undergoing heart-lung transplantation for PPH (n=11, including 3 familial cases) or secondary pulmonary hypertension (n=6) and from unused donor lungs (n=4). In situ hybridization was performed for BMPR-II mRNA. Patients were screened for the presence of mutations in BMPR2. In normal lungs, BMPR-II expression was prominent on vascular endothelium, with minimal expression in airway and arterial smooth muscle. In pulmonary hypertension cases, the intensity of BMPR-II immunostaining varied between lesions but involved endothelial and myofibroblast components. Image analysis confirmed that expression of BMPR-II was markedly reduced in the peripheral lung of PPH patients, especially in those harboring heterozygous BMPR2 mutations. A less marked reduction was also observed in patients with secondary pulmonary hypertension. In contrast, there was no difference in level of staining for TGF-betaRII or the endothelial marker CD31.
  
  
  CONCLUSIONS
  The cellular localization of BMPR-II is consistent with a role in the formation of pulmonary vascular lesions in PPH, and reduced BMPR-II expression may contribute to the process of vascular obliteration in severe pulmonary hypertension.
authors.affiliation: Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Carl
authors.initials: C
authors.lastname: Atkinson
authors.forename: Susan
authors.initials: S
authors.lastname: Stewart
authors.forename: Paul D
authors.initials: PD
authors.lastname: Upton
authors.forename: Rajiv
authors.initials: R
authors.lastname: Machado
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Thomson
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
mesh_terms: D030201:Activin Receptors, Type I / Q000096:biosynthesis; D000328:Adult; D015415:Biomarkers / Q000032:analysis; D052006:Bone Morphogenetic Protein Receptors, Type II; D004252:DNA Mutational Analysis; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006579:Heterozygote; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008168:Lung / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009928:Organ Specificity; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D011652:Pulmonary Circulation / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II