title: Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice.
abstract: We previously demonstrated the essential role of the flt-1 gene in regulating the development of the cardiovascular system. While the inactivation of the flt-1 gene leads to a very severe disorganization of the vascular system, the primary defect at the cellular level was unknown. Here we report a surprising finding that it is an increase in the number of endothelial progenitors that leads to the vascular disorganization in flt-1(-/-) mice. At the early primitive streak stage (prior to the formation of blood islands), hemangioblasts are formed much more abundantly in flt-1(-/-) embryos. This increase is primarily due to an alteration in cell fate determination among mesenchymal cells, rather than to increased proliferation, migration or reduced apoptosis of flt-1(-/-) hemangioblasts. We further show that the increased population density of hemangioblasts is responsible for the observed vascular disorganization, based on the following observations: (1) both flt-1(-/-) and flt-1(+/+) endothelial cells formed normal vascular channels in chimaeric embryos; (2) wild-type endothelial cells formed abnormal vascular channels when their population density was significantly increased; and (3) in the absence of wild-type endothelial cells, flt-1(-/-) endothelial cells alone could form normal vascular channels when sufficiently diluted in a developing embryo. These results define the primary defect in flt-1(-/-) embryos at the cellular level and demonstrate the importance of population density of progenitor cells in pattern formation.
authors.affiliation: Lawson Research Institute, St Joseph's Health Centre, Departments of Paediatrics and Biochemistry, University of Western Ontario, London, Ontario, Canada N6A 4V2. gfong@lri.stjosephs.london.on.ca
authors.forename: G H
authors.initials: GH
authors.lastname: Fong
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: D M
authors.initials: DM
authors.lastname: Bryce
authors.forename: J
authors.initials: J
authors.lastname: Peng
mesh_terms: D000818:Animals; D002319:Cardiovascular System / Q000196:embryology*; D002452:Cell Count; D002454:Cell Differentiation; D002455:Cell Division; D002678:Chimera / Q000235:genetics; D007150:Immunohistochemistry; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D013234:Stem Cells / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1; D015017:Yolk Sac / Q000166:cytology
chemical_list: D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1