title: VEGF-A signaling through Flk-1 is a critical facilitator of early embryonic lung epithelial to endothelial crosstalk and branching morphogenesis.
abstract: Vascular endothelial growth factor-A (VEGF-A) signaling directs both vasculogenesis and angiogenesis. However, the role of VEGF-A ligand signaling in the regulation of epithelial-mesenchymal interactions during early mouse lung morphogenesis remains incompletely characterized. Fetal liver kinase-1 (Flk-1) is a VEGF cognate receptor (VEGF-R2) expressed in the embryonic lung mesenchyme. VEGF-A, expressed in the epithelium, is a high affinity ligand for Flk-1. We have used both gain and loss of function approaches to investigate the role of this VEGF-A signaling pathway during lung morphogenesis. Herein, we demonstrate that exogenous VEGF 164, one of the 3 isoforms generated by alternative splicing of the Vegf-A gene, stimulates mouse embryonic lung branching morphogenesis in culture and increases the index of proliferation in both epithelium and mesenchyme. In addition, it induces differential gene and protein expression among several key lung morphogenetic genes, including up-regulation of BMP-4 and Sp-c expression as well as an increase in Flk-1-positive mesenchymal cells. Conversely, embryonic lung culture with an antisense oligodeoxynucleotide (ODN) to the Flk-1 receptor led to reduced epithelial branching, decreased epithelial and mesenchymal proliferation index as well as downregulating BMP-4 expression. These results demonstrate that the VEGF pathway is involved in driving epithelial to endothelial crosstalk in embryonic mouse lung morphogenesis.
authors.affiliation: Developmental Biology Program, Saban Research Institute, Children's Hospital Los Angeles, Department of Pediatric Surgery, USC Keck School of Medicine, 4650 Sunset Blvd., Los Angeles, CA 90027, USA.
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Del Moral
authors.forename: Frédéric G
authors.initials: FG
authors.lastname: Sala
authors.forename: Denise
authors.initials: D
authors.lastname: Tefft
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: Eli
authors.initials: E
authors.lastname: Keshet
authors.forename: Savério
authors.initials: S
authors.lastname: Bellusci
authors.forename: David
authors.initials: D
authors.lastname: Warburton
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D004727:Endothelium / Q000196:embryology / Q000378:metabolism; D004848:Epithelium / Q000196:embryology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D036341:Intercellular Signaling Peptides and Proteins; D008168:Lung / Q000098:blood supply / Q000196:embryology* / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D009024:Morphogenesis; D009924:Organ Culture Techniques; D010455:Peptides / Q000378:metabolism; D037721:Pulmonary Surfactant-Associated Protein C; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology*
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D037721:Pulmonary Surfactant-Associated Protein C; C489680:Sftpc protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2