Enhanced expression of vascular endothelial growth factor in lungs of newborn infants with congenital diaphragmatic hernia and pulmonary hypertension

Background-Pulmonary hypoplasia accompanied by pulmonary hypertension resis tant to treatment is an important feature of congenital diaphragmatic herni a (CDH). The pathogenesis of the pulmonary vascular abnormalities in CDH re mains to be elucidated at the molecular level. Vascular endothelial growth factor (VEGF), an endothelial cell specific mitogen, is known to play a rol e in pulmonary angiogenesis and vascular remodelling but there are no data on VEGF expression in patients with CDH. Methods-Necroscopic lung specimens from 21 patients with CDH with lung hypo plasia and from seven age matched control newborn infants without lung hypo plasia were processed for immunohistochemical analysis using affinity purif ied anti-human VEGF antibodies. All the cases of CDH had pulmonary hypoplas ia, indicated by a lung/body weight index of less than or equal to 0.012, a nd pulmonary hypertension indicated by repeated cardiac ultrasonography. Ce llular localisation of VEGF was semiquantitatively analysed using a stainin g score ranging from 0 (no staining) to 4 (very strong staining). Results-Significantly raised levels of VEGF immunoreactivity were observed in lung specimens from cases of CDH compared with controls. VEGF was detect ed mainly in the bronchial epithelium and the medial smooth muscle cells of large (>200 mu m) and small (<200 mu m) pulmonary arteries, the most inten se staining being in the medial smooth muscle cells of the small pulmonary arteries. Endothelial cells were positive for VEGF staining in patients wit h CDH but not in controls. Conclusions-This is the first study of VEGF expression in newborn infants w ith CDH. Increased levels of VEGF, especially in the small, pressure regula ting pulmonary arteries, point to a potential role in vascular remodelling. This may reflect an unsuccessful attempt by the developing fetus to increa se the pulmonary vascular bed in the hypoplastic lungs to alleviate the ass ociated pulmonary hypertension.