title: Flt1/VEGFR1 heterozygosity causes transient embryonic edema.
abstract: Vascular endothelial growth factor-A is a major player in vascular development and a potent vascular permeability factor under physiological and pathological conditions by binding to a decoy receptor Flt1 and its primary receptor Flk1. In this study, we show that Flt1 heterozygous (Flt1(+/-)) mouse embryos grow up to adult without life-threatening abnormalities but exhibit a transient embryonic edema around the nuchal and back regions, which is reminiscent of increased nuchal translucency in human fetuses. Vascular permeability is enhanced and an intricate infolding of the plasma membrane and huge vesicle-like structures are seen in Flt1(+/-) capillary endothelial cells. Flk1 tyrosine phosphorylation is elevated in Flt1(+/-) embryos, but Flk1 heterozygosity does not suppress embryonic edema caused by Flt1 heterozygosity. When Flt1 mutants are crossed with Aspp1(-/-) mice which exhibit a transient embryonic edema with delayed formation and dysfunction of lymphatic vessels, only 5.7% of Flt1(+/-); Aspp1(-/-) mice survive, compared to expected ratio (25%). Our results demonstrate that Flt1 heterozygosity causes a transient embryonic edema and can be a risk factor for embryonic lethality in combination with other mutations causing non-lethal vascular phenotype.
authors.affiliation: Division of Vascular Biology, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.|Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Otowa
authors.affiliation: Division of Vascular Biology, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Moriwaki
authors.affiliation: Division of Vascular Biology, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Sano
authors.affiliation: Division of Vascular Biology, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Shirakabe
authors.affiliation: Ultrastructural Research Team, RIKEN Center for Life Science Technologies, 2-3-3, Minatojima-minamimachi, Kobe, Hyogo 650-0047, Japan.
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Yonemura
authors.affiliation: Institute of Physiology and Medicine, Jobu University, 270-1 Shinmachi, Takasaki, Gunma 370-1393, Japan.
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Toronto, Ontario, M5G0A4 Canada.
authors.forename: Janet
authors.initials: J
authors.lastname: Rossant
authors.affiliation: Cancer Science Institute, National University of Singapore, Center for Translational Medicine, 14 Medical Drive, #12-01, 117599, Singapore.|International Research Center for Medical Sciences, Kumamoto University, Honjo 2-2-1, Chuo-ku, Kumamoto 860-0811, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
authors.affiliation: Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kakeji
authors.affiliation: Division of Vascular Biology, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Hirashima
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D002199:Capillary Permeability; D002462:Cell Membrane / Q000378:metabolism; D004487:Edema / Q000235:genetics* / Q000378:metabolism; D047108:Embryonic Development; D042783:Endothelial Cells; D018740:Genetic Heterogeneity; D051379:Mice; D009154:Mutation; D048208:Nuchal Translucency Measurement; D010766:Phosphorylation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics* / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C528805:Ppp1r13b protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C501163:Flt1 protein, mouse; C000592875:Kdr protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2