title: VEGF and endothelium-derived retinoic acid regulate lung vascular and alveolar development.
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.
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California; and.
authors.forename: Eun Jun
authors.initials: EJ
authors.lastname: Yun
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California; and.
authors.forename: Walter
authors.initials: W
authors.lastname: Lorizio
authors.affiliation: Pediatric Heart Lung Center and Department of Pediatrics, University of Colorado Denver-Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Gregory
authors.initials: G
authors.lastname: Seedorf
authors.affiliation: Pediatric Heart Lung Center and Department of Pediatrics, University of Colorado Denver-Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Abman
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California; and thiennu.vu@ucsf.edu.
authors.forename: Thiennu H
authors.initials: TH
authors.lastname: Vu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002196:Capillaries / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D004727:Endothelium / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; C113569:fibroblast growth factor 18; C467480:vascular endothelial growth factor A, mouse; D005346:Fibroblast Growth Factors
keywords: FGF-18; VEGF; alveolar development; alveolarization; lung development; retinoic acid; vascular development