TABLE 1.

VASCULAR ENDOTHELIAL GROWTH FACTOR IS CRUCIAL FOR ALVEOLAR DEVELOPMENT AND FULFILLS KOCH'S POSTULATE

Modified Koch's Postulate	Evidence	References
1. VEGF is present in all models of alveolarization	VEGF is identified in the lungs of various species, including mice, rats, rabbits, sheep, nonhuman primates, and humans.	20, 23, 36, 37, 50, 51
2. VEGF is detected specifically at sites of secondary crest formation	VEGF mRNA and protein are localized to distal airway epithelial cells and the basement membrane subjacent to the airway epithelial cells, suggesting that translocation of VEGF protein occurs after its synthesis in the epithelium. VEGFR-1 and VEGFR-2 mRNA expression increases during normal mouse lung development and is localized to the pulmonary endothelial cells closely apposed to the developing epithelium.	49, 50
3. VEGF inhibition blocks alveolarization	Pharmacologic (SU5416, VEGF trap, mFlt(1-3)-Ig) and genetic (targeted VEGF164 and VEGF188 exon deletion) inhibition of VEGF results in fewer and larger distal airspaces and capillary rarefaction.	7, 20, 30, 31
4. Alveolarization is enhanced when VEGF is ectopically administered	VEGF treatment (via intratracheal adenovirus–mediated gene therapy or intramuscular injection of recombinant VEGF) promotes lung angiogenesis and alveolarization in experimental, oxygen-induced BPD in newborn rats.	20, 40, 41

Definition of abbreviations: BPD = bronchopulmonary dysplasia; VEGF = vascular endothelial growth factor; VEGFR = VEGF receptor.