Structural and molecular regulation of lung maturation by intratracheal vascular endothelial growth factor administration in the normally grown and placentally restricted fetus

Key points Ablation of hypoxia signalling leads to respiratory distress syndrome (RDS). Administering vascular endothelial growth factor (VEGF) protects from RDS. Reduced surfactant maturation in the chronically hypoxaemic placentally restricted (PR) fetus is associated with altered regulation of hypoxia signalling and may predispose to RDS. We determined the effect of intratracheal VEGF administration on the expression of genes regulating vascularization, alveolarization, proliferation, inflammation, surfactant maturation and structural markers of lung maturation in the normally grown and PR fetus. Although there were relatively few effects of VEGF on gene expression, there were positive effects on structural maturation in the normally grown and PR lung. There was no effect on fetal blood pressure or fetal breathing movements. We have provided evidence that VEGF promotes structural fetal lung maturation and may result in synergistic effects if combined with current therapeutic treatments aiming to induce surfactant maturation and reduce the risk of RDS. Abstract Inhibition of hypoxia signalling leads to respiratory distress syndrome (RDS), whereas administration of vascular endothelial growth factor (VEGF), the most widely characterized hypoxia responsive factor, protects from RDS. In the lung of the chronically hypoxaemic placentally restricted (PR) fetus, there is altered regulation of hypoxia signalling. This leads to reduced surfactant maturation in late gestation and provides evidence for the increased risk of RDS in growth restricted neonates at birth. We evaluated the effect of recombinant human VEGF administration with respect to bypassing the endogenous regulation of hypoxia signalling in the lung of the normally grown and PR sheep fetus. There was no effect of VEGF administration on fetal blood pressure or fetal breathing movements. We examined the effect on the expression of genes regulating VEGF signalling (FLT1 and KDR), angiogenesis (ANGPT1, AQP1, ADM), alveolarization (MMP2, MMP9, TIMP1, COL1A1, ELN), proliferation (IGF1, IGF2, IGF1R, MKI67, PCNA), inflammation (CCL2, CCL4, IL1B, TNFA, TGFB1, IL10) and surfactant maturation (SFTP-A, SFTP-B, SFTP-C, SFTP-D, PCYT1A, LPCAT, LAMP3, ABCA3). Despite the effects of PR on the expression of genes regulating airway remodelling, inflammatory signalling and surfactant maturation, there were very few effects of VEGF administration on gene expression in the lung of both the normally grown and PR fetus. There were, however, positive effects of VEGF administration on percentage tissue, air space and numerical density of SFTP-B positive alveolar epithelial cells in fetal lung tissue. These results provide evidence for the stimulatory effects of VEGF administration on structural maturation in the lung of both the normally grown and PR fetus.