Deletion of vascular endothelial growth factor C (VEGF-C) and VEGF-D is not equivalent to VEGF receptor 3 deletion in mouse embryos.
Lymphatic vessels play an important role in the regulation of tissue fluid balance, immune responses, and fat adsorption and are involved in diseases including lymphedema and tumor metastasis. Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR-3) is necessary for development of the blood vasculature during early embryogenesis, but later, VEGFR-3 expression becomes restricted to the lymphatic vasculature. We analyzed mice deficient in both of the known VEGFR-3 ligands, VEGF-C and VEGF-D. Unlike the Vegfr3(-/-) embryos, the Vegfc(-/-); Vegfd(-/-) embryos displayed normal blood vasculature after embryonic day 9.5. Deletion of Vegfr3 in the epiblast, using keratin 19 (K19) Cre, resulted in a phenotype identical to that of the Vegfr3(-/-) embryos, suggesting that this phenotype is due to defects in the embryo proper and not in placental development. Interestingly, the Vegfr3(neo) hypomorphic mutant mice carrying the neomycin cassette between exons 1 and 2 showed defective lymphatic development. Overexpression of human or mouse VEGF-D in the skin, under the K14 promoter, rescued the lymphatic hypoplasia of the Vegfc(+/-) mice in the K14-VEGF-D; Vegfc(+/-) compound mice, suggesting that VEGF-D is functionally redundant with VEGF-C in the stimulation of developmental lymphangiogenesis. Our results suggest VEGF-C- and VEGF-D-independent functions for VEGFR-3 in the early embryo.
Molecular/Cancer Biology Laboratory, Haartman Institute, Biomedicum Helsinki and Helsinki University Central Hospital, P. O. B. 63 (Haartmaninkatu 8), University of Helsinki, 00014 Helsinki, Finland.
Paula
P
Haiko
Taija
T
Makinen
Salla
S
Keskitalo
Jussi
J
Taipale
Marika J
MJ
Karkkainen
Megan E
ME
Baldwin
Steven A
SA
Stacker
Marc G
MG
Achen
Kari
K
Alitalo
D000483:Alleles; D000818:Animals; D001808:Blood Vessels / Q000196:embryology; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000378:metabolism* / Q000473:pathology; D017353:Gene Deletion; D018390:Gene Targeting; D042583:Lymphangiogenesis; D042601:Lymphatic Vessels / Q000002:abnormalities / Q000196:embryology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D042582:Vascular Endothelial Growth Factor C / Q000172:deficiency*; D042643:Vascular Endothelial Growth Factor D / Q000172:deficiency*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000172:deficiency*
D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D040321:Vascular Endothelial Growth Factor Receptor-3