Defective Pulmonary Development in the Absence of Heparin-Binding Vascular Endothelial Growth Factor Isoforms

Abstract

Development of the airways, alveoli, and the pulmonary vasculature in the fetus is a process that is precisely controlled. One of the growth factors involved, vascular endothelial growth factor (VEGF), is so critical for embryonic development that in the mouse, elimination of just a single allele is lethal. In the early stages of lung development, the mouse VEGF gene expresses three isoforms (120, 164, and 188) in a distinct temporo-spatial pattern, suggesting a specific function for each. We engineered mice that express only VEGF 120, to study the role of VEGF isoforms in lung development. Lung vessel development in these mice was studied by scanning electron microscopy of Mercox casts of lung vasculature. Airway and air-blood barrier development was analyzed by light microscopy, transmission electron microscopy, immunohistochemistry, and morphometry. In all VEGF120/120 fetuses and pups, lung vascular casts were smaller and less dense compared with 120/+ and wild-type littermates. Although the generation count of pre-acinar vessels was similar in all three genotypes, the most peripheral vessels were dilated and were more widely separated in 120/120 fetuses of all ages, compared with 120/+ and wild-type littermates. In addition, 120/120 animals had fewer air-blood barriers and a decreased airspace-parenchyma ratio compared with 120/+ and wild-type littermates. We concluded that the absence of VEGF 164 and 188 isoforms impairs lung microvascular development and delays airspace maturation, indicating an essential role for heparin-binding VEGF isoforms in normal lung development.

Pentoxifylline and prevention of hyperoxia-induced lung ­injury in neonatal rats

“…Our study demonstrated that PTX treatment during hyperoxia is able to markedly increase pulmonary vascular density, which may be induced by increased VEGF expression. We found that VEGF121 expression was constant in all three study groups, indicating that VEGF121 may not be influenced by oxygen stress as seen in a rabbit model (28). Previous studies have shown that VEGF121 is a predominant form before embryonic day 14, indicating that this isoform has a unique role early in lung development (29), with perhaps a less important role toward birth, leading to a decreased expression and a lack of response during oxygen exposure.…”

“…Different isoforms have different affinities for heparin and receptors, and distinct tempo-spatial expression of these isoforms suggests different function. Mice expressing only VEGF121 had impaired lung vascular and airspace formation, indicating an essential role for the heparin sulfate-binding VEGF165 and VEGF189 isoforms in lung development (28). In our study, we demonstrated that PTX protects against hyperoxia-induced (13).…”

Epoxyeicosanoids promote organ and tissue regeneration

“…Several studies support the notion that ECs within the lungs actively promote normal alveolar growth and lung regeneration (15). Conversely, genetic or pharmacological antagonism of the VEGF nitric oxide pathway can lead to decreased lung angiogenesis and poor lung regeneration (41). Similar to the liver and lung regeneration discussed above, kidney blood vessels appear to have a role in kidney regeneration (42).…”

Response of vascular endothelial growth factor and angiogenesis-related genes to stepwise increases in inspired oxygen in neonatal rat lungs

“…Microvascular development, which is essential for efficient gas exchange, is regulated by vascular endothelial growth factor (VEGF), which has been shown to be disrupted in BPD (12)(13)(14). Exposure to high concentrations of oxygen during lung development results in lung injury characterized by alterations in capillary density, endothelial cell destruction, pulmonary inflammation, and inhibition of the process of alveolarization (15)(16)(17)(18)(19).…”

“…VEGF is a potent, endothelial cell mitogen that stimulates vessel proliferation, migration, and tube formation leading to angiogenic growth of new blood vessels (15)(16)(17)(18)(19). It is essential for angiogenesis during development; the deletion of a single allele arrests angiogenesis and causes embryonic lethality (20)(21)(22).…”