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.
Highlights
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 Flt[1] and its primary receptor Flk[1]
Vascular endothelial growth factor (VEGF)-A is a major player in all aspects of vascular development and is a potent vascular permeability factor that is involved in fluid homeostasis under physiological and pathological conditions[1,2,3]
VEGF-A haploinsufficiency in mice resulted in embryonic lethality associated with defective blood vessel development[9,10], whereas a hypermorphic allele of VEGF-A gene produced severe abnormalities in heart development and embryonic lethality[11], indicating that a subtle change of VEGF-A protein levels affects vascular function during mouse embryogenesis
Summary
Flt1+/− mice showed a transient embryonic edema without overt defects in cardiovascular development. Assessing the leakage of intravenously-injected Evans blue dye after topical application of mustard oil This analysis showed that vascular permeability is comparable between WT and Flt1+/− adult mice (Supplementary Fig. S5), suggesting that the enhancement of vascular permeability is restricted to embryonic development in Flt1+/− mice. When Aspp[1] mutants were crossed with Flt1TK mutants, Flt1+/TK; Aspp1−/− mice survived to adult at a normal Mendelian frequency (Table 1B) These results suggest that both lymphatic dysfunction and enhanced vascular permeability are responsible for stronger edema formation and lethality of Flt1+/−; Aspp1−/− embryos. They have been reported that Src plays a role in VEGF-A-induced vascular permeability[19,20,21,22] and that ASPP and Src play a cooperative role in epithelial organization in Drosophila[28]. Combined defects in pathways affecting vascular permeability and lymphatic drainage could lead to fetal loss
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