title: Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis.
abstract: Pulmonary arteries of patients with severe pulmonary hypertension (SPH) presenting in an idiopathic form (primary PH-PPH) or associated with congenital heart malformations or collagen vascular diseases show plexiform lesions. It is postulated that in lungs with SPH, endothelial cells in plexiform lesions express genes encoding for proteins involved in angiogenesis, in particular, vascular endothelial growth factor (VEGF) and those involved in VEGF receptor-2 (VEGFR-2) signalling. On immunohistochemistry and in situ hybridization, endothelial cells in the plexiform lesions expressed VEGF mRNA and protein and overexpressed the mRNA and protein of VEGFR-2, and the transcription factor subunits HIF-1alpha and HIF-1beta of hypoxia inducible factor, which are responsible for the hypoxia-dependent induction of VEGF. When compared with normal lungs, SPH lungs showed decreased expression of the kinases PI3 kinase and src, which, together with Akt, relay the signal transduction downstream of VEGFR-2. Because markers of angiogenesis are expressed in plexiform lesions in SPH, it is proposed that these lesions may form by a process of disordered angiogenesis.
authors.affiliation: Department of Pathology, Division of Pulmonary Sciences and Critical Care Medicine, Pulmonary Hypertension Center, University of Colorado Health Sciences Center, Colorado, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Tuder
authors.forename: M
authors.initials: M
authors.lastname: Chacon
authors.forename: L
authors.initials: L
authors.lastname: Alger
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: L
authors.initials: L
authors.lastname: Taraseviciene-Stewart
authors.forename: Y
authors.initials: Y
authors.lastname: Kasahara
authors.forename: C D
authors.initials: CD
authors.lastname: Cool
authors.forename: A E
authors.initials: AE
authors.lastname: Bishop
authors.forename: M
authors.initials: M
authors.lastname: Geraci
authors.forename: G L
authors.initials: GL
authors.lastname: Semenza
authors.forename: M
authors.initials: M
authors.lastname: Yacoub
authors.forename: J M
authors.initials: JM
authors.lastname: Polak
authors.forename: N F
authors.initials: NF
authors.lastname: Voelkel
mesh_terms: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D015415:Biomarkers / Q000032:analysis; D016022:Case-Control Studies; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors / Q000032:analysis* / Q000235:genetics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017403:In Situ Hybridization / Q000379:methods; D008222:Lymphokines / Q000032:analysis* / Q000235:genetics; D009389:Neovascularization, Pathologic; D009842:Oligopeptides / Q000032:analysis; D019869:Phosphatidylinositol 3-Kinases / Q000032:analysis; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis* / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon; D017978:Receptors, Growth Factor / Q000032:analysis* / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor; D014157:Transcription Factors / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: C497396:ARNT protein, human; D015415:Biomarkers; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D009842:Oligopeptides; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D017978:Receptors, Growth Factor; C040475:Src peptide; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D019869:Phosphatidylinositol 3-Kinases; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor