Vascular Endothelial Growth Factor as Molecular Target for Bronchopulmonary Dysplasia Prevention in Very Low Birth Weight Infants

Abstract

Bronchopulmonary dysplasia (BPD) still represents an important burden of neonatal care. The definition of the disease is currently undergoing several revisions, and, to date, BPD is actually defined by its treatment rather than diagnostic or clinic criteria. BPD is associated with many prenatal and postnatal risk factors, such as maternal smoking, chorioamnionitis, intrauterine growth restriction (IUGR), patent ductus arteriosus (PDA), parenteral nutrition, sepsis, and mechanical ventilation. Various experimental models have shown how these factors cause distorted alveolar and vascular growth, as well as alterations in the composition and differentiation of the mesenchymal cells of a newborn's lungs, demonstrating a multifactorial pathogenesis of the disease. In addition, inflammation and oxidative stress are the common denominators of the mechanisms that contribute to BPD development. Vascular endothelial growth factor-A (VEGFA) constitutes the most prominent and best studied candidate for vascular development. Animal models have confirmed the important regulatory roles of epithelial-expressed VEGF in lung development and function. This educational review aims to discuss the inflammatory pathways in BPD onset for preterm newborns, focusing on the role of VEGFA and providing a summary of current and emerging evidence.

Keywords: BPD; VEGFA; biomarker; inflammation; lung disease; oxidative stress; preterm.

Figure 1

Schematic representation of risk factors associated with bronchopulmonary dysplasia.

Figure 2

Schematic representation of free radical generation during phagocyte activation. Following injury, due to infection, hypoxia–ischemia, or hyperoxia, neutrophils release ROS. The superoxide anion (^·O₂⁻), the most abundant radical species, is the first stage of bacterial killing reaction, which is followed by generation of other ROS, such as hydroxyl radical (^·OH) by free irons and hypochlorous acid (OHCL⁻) by myeloperoxidases.

Figure 3

Schematic representation of free radical generation during hypoxia–reoxygenation. Hypoxanthine derives from degradation of adenosine 5′-triphosphate (ATP) during hypoxia-induced anaerobic metabolism. During reoxygenation, xanthine oxidoreductase catalyzes hydroxylation of hypoxanthine to xanthine and uric acid, inducing the release of ROS. Xanthine oxidoreductase exists in two forms: xanthine dehydrogenase and xanthine oxidase. An irreversible proteolytic conversion of xanthine dehydrogenase to xanthine oxidase can also be specifically induced by IFN-γ in lung microvascular endothelial cells.

Figure 4

Diet supplementation and vascular development. Supplementation with probiotics and PUFA ω-3 affect endothelial cell recruitment, vessel formation and dilatation, vascular permeability, and vascularization.