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N. Lara, S.E. Aparicio, S. Sawant, C.J. Barnstable, B. Chang, J. Tombran–Tink; Regulation of Factors Controlling the Onset of Neovascularization in the Vldlr Mutant Mouse . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3155.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: A nonsense mutation in the very low density lipid receptor, Vldlr, gene in the mouse results in an early onset retinal neovascular phenotype. In homozygous B6;129–Vldlr tm1Her[r], elaboration of subretinal vasculature with anastomosis to choroidal vessels occurs at 6 weeks postnatal age and subretinal hemorrhaging is evident with increasing age (Heckenlively et al., (2003) Retina, 23,518). The aim of this study is to examine the expression of key factors that initiate and inhibit retinal angiogenesis in this mutant. Methods: Retinas from B6;129–Vldlr tm1Her[r] animals were dissected at 3 weeks PN age when the retinas are healthy and at 2 months when retinochoroidal neovascular vessels and neovascular leakage are prominent features of the retina. Retinas were processed for RNA extraction and transcriptional expression of pro– and anti–angiogenic factors examined by RT–PCR. Results: The angiogenesis inhibitors PEDF, TIMP–2, and TIMP–3 and promoters VEGF–A, VEGF–R1, VEGF–R2, MMP–8, and MMP14 were clearly expressed in Vldlr mutant retinas at 3 weeks of age. Levels of TSP1, TSP2, and MMP–13 were undetectable at 3 weeks. At 2 months, during active neovascular episodes in the Vldlr mutant retina, expression of the angiogenesis inhibitor, PEDF dropped to barely detectable levels, TSP1 and TSP2 expression were dramatically elevated, and no significant changes were observed in TIMP–2 and TIMP–3. In contrast to the decreased levels of PEDF, a strong upregulation of VEGF–R1, VEGF–R2, MMP–8, MMP–13 and MMP–14 was observed in the 2 months old Vldlr retinas. Changes in the transcription of VEGF–A were not detected at these two stages. Conclusions: The strong decrease in expression of the key anti–angiogenic factor PEDF and high expression of multiple angiogenic promoters during active neovascular episodes in the Vldlr mutants demonstrate that this model could be used to further dissect molecular cascades that trigger the onset of retinal angiogenesis and is the first reliable genetically–determined model that could be used to study the effects of potential anti–angiogenic drugs.
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