Lymphangiogenesis in the developing lung promoted by VEGF-A.

Understanding the basic processes of late-stage pulmonary vascular development is essential as this period corresponds to the stage when preterm infants have increased chance of survival. During this period, refinement of the gas exchange unit leads to close apposition of the capillary vasculature and airway epithelium through thinning of the mesenchyme, formation of alveolar septae and functional adaptation of endothelial cells into vessels including pulmonary lymphatics. The pulmonary lymphatic network promotes efficient gas exchange through maintaining interstitial fluid balance. Through conditional transgene regulation, we found that a modest, pathologically relevant increase in vascular endothelial growth factor A (VEGF-A) in distal lung during only the perinatal period adversely affected final refinement of the gas exchange unit. VEGF-A induction disrupted the established vascular network, increased endothelial cell number, altered endothelial ultrastructure and reduced mesenchymal thinning. In addition, VEGF-A induction caused a 3-fold increase in small vessels identified as lymphatics in distal lung. mRNA levels of lymphangiogenic factors VEGF-D/-C were unchanged, while levels of the cognate receptor VEGFR-3 increased. The responses to VEGF-A induction in the perinatal period differ from those during early lung development when endothelial migration, but not proliferation altered initial vascular patterning (Akeson, A.L., Greenberg, J.M., Cameron, J.E., Thompson, F.Y., Brooks, S.K., Wiginton, D., Whitsett, J.A., 2003. Temporal and spatial regulation of VEGF-A controls vascular patterning in the embryonic lung. Dev. Biol. 264, 443-455). The late-stage response resembles that of adult lung to VEGF-inducing stimuli including injury and disease. These data suggest that VEGF-A influences the balance between development of blood and lymphatic vasculature during lung organogenesis.