The Expression of Vascular Endothelial Growth Factor and Its Receptors in Congenital Bronchopulmonary Cystic Malformations

Abstract

Background Bronchopulmonary sequestration (BPS) and congenital cystic adenomatoid malformation (CCAM) represent rare hamartomatous abnormalities of the lung. Dysregulation of cytokines that influence pulmonary vasculogenesis and epithelial growth, both known to be altered in BPS and CCAM, may play a role in their pathogenesis.

Objective We hypothesized that expression of vascular endothelial growth factor (VEGF) or its receptors might be altered in CCAM and BPS, possibly distinguishing CCAM from BPS, or from controls.

Methods Lung biopsy specimens obtained from infants who had undergone surgery for BPS (n = 4) or CCAM (n = 5) within the first month of life and normal lung autopsy samples (n = 4) serving as controls were investigated immunohistochemically for the protein expression levels of VEGF and its corresponding receptors.

Results VEGF, vascular endothelial growth factor receptor 1 (VEGFR1), vascular endothelial growth factor receptor 2 (VEGFR2), and vascular endothelial growth factor receptor 3 (VEGFR3) staining was detected in CCAM and BPS specimens, as well as in control samples. VEGFR2 expression increased from controls to CCAM and from CCAM to BPS, the difference between controls and BPS being significant. The expression of VEGF, VEGFR1, and VEGFR3 was similar among the three groups. Consistent with a possible involvement of VEGFR2 in altered vasculogenesis-bronchiogenesis interaction, its expression was predominantly found in bronchial but not alveolar regions.

Conclusions The data suggest a possible role of VEGF-VEGFR2 interaction in the pathogenesis of congenital bronchopulmonary cystic malformations. However, VEGFR2 does not represent a suitable histochemical marker to distinguish between BPS and CCAM.

Keywords

congenital cystic adenomatoid malformation - bronchopulmonary sequestration - vascular endothelial growth factor receptor 2

• References

• 1 Bush A. Prenatal presentation and postnatal management of congenital thoracic malformations. Early Hum Dev 2009; 85 (11) 679-684
• 2 Cass DL, Quinn TM, Yang EY , et al. Increased cell proliferation and decreased apoptosis characterize congenital cystic adenomatoid malformation of the lung. J Pediatr Surg 1998; 33 (7) 1043-1046 , discussion 1047
• 3 Clements BS, Warner JO. Pulmonary sequestration and related congenital bronchopulmonary-vascular malformations: nomenclature and classification based on anatomical and embryological considerations. Thorax 1987; 42 (6) 401-408
• 4 Liechty KW, Crombleholme TM, Quinn TM, Cass DL, Flake AW, Adzick NS. Elevated platelet-derived growth factor-B in congenital cystic adenomatoid malformations requiring fetal resection. J Pediatr Surg 1999; 34 (5) 805-809 , discussion 809–810
• 5 Souza P, Sedlackova L, Kuliszewski M , et al. Antisense oligodeoxynucleotides targeting PDGF-B mRNA inhibit cell proliferation during embryonic rat lung development. Development 1994; 120 (8) 2163-2173
• 6 Walford N, Htun K, Chen J, Liu YY, Teo H, Yeo GS. Intralobar sequestration of the lung is a congenital anomaly: anatomopathological analysis of four cases diagnosed in fetal life. Pediatr Dev Pathol 2003; 6 (4) 314-321
• 7 Farrugia MK, Raza SA, Gould S, Lakhoo K. Congenital lung lesions: classification and concordance of radiological appearance and surgical pathology. Pediatr Surg Int 2008; 24 (9) 987-991
• 8 Morrisey EE, Hogan BL. Preparing for the first breath: genetic and cellular mechanisms in lung development. Dev Cell 2010; 18 (1) 8-23
• 9 Voelkel NF, Vandivier RW, Tuder RM. Vascular endothelial growth factor in the lung. Am J Physiol Lung Cell Mol Physiol 2006; 290 (2) L209-L221
• 10 Le Cras TD, Spitzmiller RE, Albertine KH, Greenberg JM, Whitsett JA, Akeson AL. VEGF causes pulmonary hemorrhage, hemosiderosis, and air space enlargement in neonatal mice. Am J Physiol Lung Cell Mol Physiol 2004; 287 (1) L134-L142
• 11 Tang K, Rossiter HB, Wagner PD, Breen EC. Lung-targeted VEGF inactivation leads to an emphysema phenotype in mice. J Appl Physiol 2004; 97 (4) 1559-1566 , discussion 1549
• 12 Kasahara Y, Tuder RM, Taraseviciene-Stewart L , et al. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest 2000; 106 (11) 1311-1319
• 13 Weber SC, Rheinlaender C, Sarioglu N , et al. The expression of VEGF and its receptors in the human ductus arteriosus. Pediatr Res 2008; 64 (4) 340-345
• 14 Corbett HJ, Humphrey GM. Pulmonary sequestration. Paediatr Respir Rev 2004; 5 (1) 59-68
• 15 Cébe-Suarez S, Zehnder-Fjällman A, Ballmer-Hofer K. The role of VEGF receptors in angiogenesis; complex partnerships. Cell Mol Life Sci 2006; 63 (5) 601-615
• 16 Liu Y, Cox SR, Morita T, Kourembanas S. Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells. Identification of a 5′ enhancer. Circ Res 1995; 77 (3) 638-643
• 17 Tschirch E, Weber B, Koehne P , et al. Vascular endothelial growth factor as marker for tissue hypoxia and transfusion need in anemic infants: a prospective clinical study. Pediatrics 2009; 123 (3) 784-790