title: Egr-1 expression during neointimal development in flow-associated pulmonary hypertension.
abstract: In flow-associated pulmonary arterial hypertension (PAH), increased pulmonary blood flow is an essential trigger for neointimal formation. Using microarray analysis, we recently found that the early growth response protein 1 (Egr-1) transcription factor is increased in experimental flow-associated end-stage PAH. Its role in PAH development is unknown. Here, we assessed the spatiotemporal expression of Egr-1 during neointimal development in flow-associated PAH. Flow-associated PAH was produced in rats by combining monocrotaline administration with an aortocaval shunt. Animals were sacrificed 1 day before or 1 day, 1 week, or 4 to 5 weeks after flow addition. Egr-1 expression was spatiotemporally assessed using laser microdissection, quantitative real-time PCR and immunohistochemistry. In addition, Egr-1 expression was assessed in a non-neointimal pulmonary hypertension model and in human PAH associated with congenital shunt. In 4 to 5 weeks, rats subjected to increased flow developed PAH with neointimal lesions. Egr-1 mRNA was increased 1 day after flow addition and in end-stage PAH, whereas monocrotaline only did not result in increased Egr-1 mRNA. Directly after flow addition, Egr-1 was expressed in endothelial cells. During disease development, Egr-1 protein expression increased and migrated throughout the vessel wall. In PAH patients, Egr-1 was expressed in vessels with media hypertrophy and neointimal lesions, including plexiform lesions. Thus, Egr-1 may be an important regulator in the development of pulmonary neointimal lesions induced by increased pulmonary blood flow.
authors.affiliation: Center for Congenital Heart Diseases, Department of Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. m.g.dickinson@umcg.nl
authors.forename: Michael G
authors.initials: MG
authors.lastname: Dickinson
authors.forename: Beatrijs
authors.initials: B
authors.lastname: Bartelds
authors.forename: Grietje
authors.initials: G
authors.lastname: Molema
authors.forename: Marinus A
authors.initials: MA
authors.lastname: Borgdorff
authors.forename: Bibiche
authors.initials: B
authors.lastname: Boersma
authors.forename: Janny
authors.initials: J
authors.lastname: Takens
authors.forename: Michel
authors.initials: M
authors.lastname: Weij
authors.forename: Pieter
authors.initials: P
authors.lastname: Wichers
authors.forename: Hannie
authors.initials: H
authors.lastname: Sietsma
authors.forename: Rolf M F
authors.initials: RM
authors.lastname: Berger
mesh_terms: D000818:Animals; D001166:Arteriovenous Shunt, Surgical; D001783:Blood Flow Velocity / Q000502:physiology; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D065627:Familial Primary Pulmonary Hypertension; D006330:Heart Defects, Congenital / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D006439:Hemodynamics / Q000502:physiology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D007150:Immunohistochemistry; D016686:Monocrotaline / Q000633:toxicity; D058426:Neointima / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000378:metabolism
chemical_list: D051766:Early Growth Response Protein 1; C094815:NAB1 protein, human; C491000:NAB2 protein, human; D012097:Repressor Proteins; D016686:Monocrotaline