Mesenchymal expression of vascular endothelial growth factors D and A defines vascular patterning in developing lung.
The lung has specific vascular patterning requirements for effective gas exchange at birth, including alignment of airways and blood vessels and lymphatic vessels. Vascular endothelial growth factors (VEGF) are potent effectors of vascular development. We examined the temporal and spatial expression of VEGF-D and specific VEGF-A isoforms at each stage of lung development. VEGF-D, expressed only by cadherin-11-positive cells of the mesenchyme, is first detected at embryonic day (E) 13.5, a period of active vasculogenesis. VEGFR-3, its cognate receptor, is detected earlier on days E11.5 to E14.5, in both blood vessels and lymphatic vessels and later, on day E17.5, in only lymphatic vessels. VEGF-A is expressed in the mesenchyme throughout lung development and also by the epithelium midway through organogenesis. Before E14, the predominant forms of VEGF-A are the soluble isoforms, VEGF-A120 and 164. Not until E14.5 do epithelial cells at the tips of expanding airways express VEGF-A, including VEGF-A188, an isoform with high affinity for extracellular matrix. Our results demonstrate unique temporal and spatial expression of VEGF-D and specific VEGF-A isoforms during lung development and suggest these related factors have distinct functions in vascular and lymphatic patterning of the lung.
Division of Pulmonary Biology, Children's Hospital Research Foundation, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA. james.greenberg@chmcc.org
James M
JM
Greenberg
Felisa Y
FY
Thompson
Sherry K
SK
Brooks
John M
JM
Shannon
Kathleen
K
McCormick-Shannon
James E
JE
Cameron
Bradford P
BP
Mallory
Ann L
AL
Akeson
D000818:Animals; D015152:Blotting, Northern; D015820:Cadherins / Q000096:biosynthesis; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism; D008168:Lung / Q000196:embryology* / Q000378:metabolism; D008222:Lymphokines / Q000737:chemistry / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D020033:Protein Isoforms; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042643:Vascular Endothelial Growth Factor D; D042442:Vascular Endothelial Growth Factors
D015820:Cadherins; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D020033:Protein Isoforms; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042643:Vascular Endothelial Growth Factor D; D042442:Vascular Endothelial Growth Factors; C086960:osteoblast cadherin; D012313:RNA; D040262:Receptors, Vascular Endothelial Growth Factor