title: Flt1 and Flk1 mediate regulation of intraocular pressure and their double heterozygosity causes the buphthalmia in mice.
abstract: Flt1 and Flk1 are receptor tyrosine kinases for vascular endothelial growth factor-A which play a crucial role in physiological and pathological angiogenesis. To study genetic interaction between the Flt1 and Flk1 genes, we crossed between Flt1 and Flk1 heterozygous (Flt1(+/-) and Flk1(+/-)) mice. We found that Flt1; Flk1 double heterozygous (Flt1(+/-); Flk1(+/-)) mice showed enlarged eyes similar to the buphthalmia detected in human congenital glaucoma with elevation of intraocular pressure (IOP). Actually, IOP was elevated in Flt1(+/-); Flk1(+/-) mice and also in Flt1 or Flk1 single heterozygous mice. However, none of these mutants showed hallmarks of glaucoma such as ganglion cell death and excavation of optic disc. To clarify the pathological causes for enlarged eyes and elevated IOP, we investigate the mice from matings between Flt1(+/-) and Flk1(+/-) mice. Flt1(+/-) mice showed enlarged Schlemm's canal and disordered collagen fibers in the sclera, whereas Flk1(+/-) mice showed atrophied choriocapillaris in the choroid. These tissues are a part of the main outflow and alternative uveoscleral outflow pathway of the aqueous humor, suggesting that these pathological changes found in Flt1(+/-) and Flk1(+/-) mice are associated with the buphthalmia in Flt1(+/-); Flk1(+/-) mice.
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.forename: Osamu
authors.initials: O
authors.lastname: Katsuta
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shirae
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kubota
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Ema
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Nakamura
authors.forename: Masanori
authors.initials: M
authors.lastname: Hirashima
mesh_terms: D000818:Animals; D006579:Heterozygote; D006871:Hydrophthalmos / Q000235:genetics* / Q000473:pathology; D007429:Intraocular Pressure / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D012590:Sclera / Q000002:abnormalities / Q000473:pathology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics*
chemical_list: C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2