VEGF and endothelium-derived retinoic acid regulate lung vascular and alveolar development

Am J Physiol Lung Cell Mol Physiol. 2016 Feb 15;310(4):L287-98. doi: 10.1152/ajplung.00229.2015. Epub 2015 Nov 13.

Abstract

Prevention or treatment of lung diseases caused by the failure to form, or destruction of, existing alveoli, as observed in infants with bronchopulmonary dysplasia and adults with emphysema, requires understanding of the molecular mechanisms of alveolar development. In addition to its critical role in gas exchange, the pulmonary circulation also contributes to alveolar morphogenesis and maintenance by the production of paracrine factors, termed "angiocrines," that impact the development of surrounding tissue. To identify lung angiocrines that contribute to alveolar formation, we disrupted pulmonary vascular development by conditional inactivation of the Vegf-A gene during alveologenesis. This resulted in decreased pulmonary capillary and alveolar development and altered lung elastin and retinoic acid (RA) expression. We determined that RA is produced by pulmonary endothelial cells and regulates pulmonary angiogenesis and elastin synthesis by induction of VEGF-A and fibroblast growth factor (FGF)-18, respectively. Inhibition of RA synthesis in newborn mice decreased FGF-18 and elastin expression and impaired alveolarization. Treatment with RA and vitamin A partially reversed the impaired vascular and alveolar development induced by VEGF inhibition. Thus we identified RA as a lung angiocrine that regulates alveolarization through autocrine regulation of endothelial development and paracrine regulation of elastin synthesis via induction of FGF-18 in mesenchymal cells.

Keywords: FGF-18; VEGF; alveolar development; alveolarization; lung development; retinoic acid; vascular development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Capillaries / metabolism
  • Cells, Cultured
  • Endothelial Cells / metabolism*
  • Endothelium / metabolism*
  • Fibroblast Growth Factors / metabolism*
  • Lung / metabolism*
  • Mice, Transgenic
  • Neovascularization, Physiologic
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • Vascular Endothelial Growth Factor A
  • fibroblast growth factor 18
  • vascular endothelial growth factor A, mouse
  • Fibroblast Growth Factors