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Keiko Fujikawa, Kaoru Inoue, Takae Koshiyama, Reiko Yamagishi, Makoto Aihara; Characterization of Vav2/3-deficient mice with spontaneous IOP elevation. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5642.
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© ARVO (1962-2015); The Authors (2016-present)
We previously described that deficiency of Vav proteins leads to an ocular phenotype in mice similar to human angle closure glaucoma, which shows early onset of iridocorneal angle changes and elevated intraocular pressure (IOP). The Vav proteins are the best-characterized guanine nucleotide exchange factors for Rho GTPases, which regulate actin cytoskeleton, migration, adhesion, and involved in rhythm. We demonstrate more precise analysis of Vav2/3-deficienct and Vav2-deficient phenotype, particularly of IOP, and of influence on circadian rhythm. In the end, we aim to evaluate spontaneously IOP-elevated mouse model for human glaucoma investigation.
We used the microneedle methods to measure IOPs of Vav2/3-deficient mice at 14, 20, 22 week and Vav2-deficient mice at 13 and 21 week respectively every 2 weeks. Concerning the 24-hour circadian rhythm, twice (day and night) IOP measurements with TonoLab rebound tonometer were carried out on Vav2/3, Vav2, and Vav3-deficient mice (Vav2/3KO, Vav2KO, Vav3KO) for 5 days. IOP elevation of Vav2/3KO and Vav2KO mice was evaluated compared to those of age-matched wild type mice. Differences between any groups were regarded as significant when they indicate above wild type IOP+2×S.D. With frozen sectioning samples, anterior ocular chamber and optic nerve head degeneration were examined.
With microneedle methods, 29.4%(5/17) of Vav2/3KO and 33.3%(4/12) of Vav2KO mice show IOP elevation, respectively. Among Vav2/3KO and Vav2KO mice, IOPs of elevated-IOP groups indicated 28.8 ± 6.9 and 19.8 ± 1.9mmHg, while those of non elevated-IOP groups were 15.4 ± 1.2 and 15.6 ± 0.8mmHg, respectively. In elevated-IOP groups of Vav2/3 and Vav2 KO mice, iridocorneal angle closures, optic nerve head cupping, and thinner of nerve fiber layer were demonstrated. In addition, some of elevated-IOP mice showed leucoma of cornea, buphthalmos, and phthysis bulbi. Once IOP elevated, mice continuously maintain its high level of IOP until at least 28 week-old ages.Investigation of the IOP circadian rhythm in Vav2/3KO, Vav2KO and Vav3KO mice, reveals two-phases with IOP elevation at night similar to that of normal mice.
Vav2/3 and Vav2-deficient mice show ocular hypertension due to ocular anterior chamber abnormalities and consequently cause glaucomatous optic neuropathy. Therefore, as an animal model of spontaneous ocular hypertension, Vavs-deficient mice serve a valuable tool.
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