Expression of vascular endothelial growth factor and Flk-1 in developing and glucocorticoid-treated mouse lung.
Although the endothelial cell is the most abundant cell type in the differentiated lung, little is known about regulation of lung developmental vasculogenesis. Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen and angiogenic factor that has putative roles in vascular development. Mitogenic actions of VEGF are mediated by the tyrosine kinase receptor KDR/murine homologue fetal liver kinase Flk-1. HLF (hypoxia-inducible factor-like factor) is a transcription factor that increases VEGF gene transcription. Dexamethasone augments lung maturation in fetal and postnatal animals. However, in vitro studies suggest that dexamethasone blocks induction of VEGF. The objectives for the current study were to measure VEGF mRNA and Flk-1 mRNA in developing mouse lung and to measure the effects of dexamethasone treatment in vivo on VEGF and Flk-1 in newborn mouse lung. Our results show that VEGF and Flk-1 messages increase in parallel during normal lung development (d 13 embryonic to adult) and that the distal epithelium expresses VEGF mRNA at all ages examined. Dexamethasone (0.1-5.0 mg x kg(-1) x d(-1)) treatment of 6-d-old mice resulted in significantly increased VEGF, HLF, and Flk-1 mRNA. Dexamethasone did not affect cell-specific expression of VEGF, VEGF protein, or proportions of VEGF mRNA splice variants. These data suggest that the developing alveolar epithelium has an important role in regulating alveolar capillary development. In addition, unlike effects on cultured cells, dexamethasone, even in relatively high doses, did not adversely affect VEGF expression in vivo. The relatively high levels of VEGF and Flk-1 mRNA in adult lung imply a role for pulmonary VEGF in endothelial cell maintenance or capillary permeability.
Bhatt
A J
AJ
Strong Children's Research Center (Division of Neonatology), Children's Hospital at Strong, University of Rochester School of Medicine, New York, USA.
Amin
S B
SB
Chess
P R
PR
Watkins
R H
RH
Maniscalco
W M
WM
D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006128:Growth / Q000187:drug effects; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D017978:Receptors, Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D003907:Dexamethasone; D016228:Endothelial Growth Factors; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D009687:Nuclear Proteins; D012333:RNA, Messenger; D020794:Receptor Protein-Tyrosine Kinases; D017978:Receptors, Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse