title: Expression of hypoxia-inducible factors, regulators, and target genes in congenital diaphragmatic hernia patients.
abstract: Congenital diaphragmatic hernia (CDH) is associated with lung hypoplasia and pulmonary hypertension and has high morbidity and mortality rates. The cause and pathophysiology of CDH are not fully understood. However, impaired angiogenesis appears to play an important role in the pathophysiology of CDH. Therefore, we examined different components of an important pathway in angiogenesis: hypoxia-inducible factors (HIFs); HIF regulators von Hippel-Lindau (VHL) and prolyl 3-hydroxylase (PHD3); and HIF target genes vascular endothelial growth factor A ( VEGF-A ) and vascular endothelial growth factor receptor 2 ( VEGFR-2 ). Quantitative polymerase chain reaction of lung tissue showed a significantly decreased expression of VEGF-A mRNA in the alveolar stage of lung development in CDH patients compared with matched control patients. In the canalicular stage, no differences for VEGF-A were seen between the lungs of CDH patients and those of control patients. Other components of angiogenesis (VHL, HIF-1α, HIF-2α, HIF-3α, VEGFR-2 mRNA, PHD3 protein) that were analyzed showed no differences in expression between CDH and control patients, independent of the developmental stage. A lower expression of VEGF mRNA in CDH patients in the alveolar stage, possibly as a result of downregulation of HIF-2α might indicate a role for these factors in the pathophysiology of CDH.
authors.affiliation: Department of Pediatric Surgery, Erasmus MC-Sophia, Rotterdam, The Netherlands.
authors.forename: Irene W J M
authors.initials: IW
authors.lastname: van der Horst
authors.forename: Prapapan
authors.initials: P
authors.lastname: Rajatapiti
authors.forename: Paul
authors.initials: P
authors.lastname: van der Voorn
authors.forename: Francien H
authors.initials: FH
authors.lastname: van Nederveen
authors.forename: Dick
authors.initials: D
authors.lastname: Tibboel
authors.forename: Robbert
authors.initials: R
authors.lastname: Rottier
authors.forename: Irwin
authors.initials: I
authors.lastname: Reiss
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
mesh_terms: D018507:Gene Expression Regulation, Developmental; D005865:Gestational Age; D006548:Hernia, Diaphragmatic / Q000235:genetics / Q000378:metabolism; D065630:Hernias, Diaphragmatic, Congenital; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007231:Infant, Newborn; D008168:Lung / Q000002:abnormalities / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000235:genetics; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D011393:Procollagen-Proline Dioxygenase; C030606:proline, 2-oxoglutarate 3-dioxygenase; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D040301:Vascular Endothelial Growth Factor Receptor-2; C497446:VHL protein, human