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.

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Keywords Congenital diaphragmatic hernia, Hypoxia-inducible factors, Lung development, Prolyl 4-hydroxylase, Vascular endothelial growth factor, Von Hippel-Lindau protein
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Journal Pediatric and Developmental Pathology
van der Horst, I.W.J.M, Rajatapiti, P, van der Voorn, P, van Nederveen, F.H, Tibboel, D, Rottier, R.J, … de Krijger, R.R. (2011). Expression of hypoxia-inducible factors, regulators, and target genes in congenital diaphragmatic hernia patients. Pediatric and Developmental Pathology, 14(5), 384–390. doi:10.2350/09-09-0705-OA.1