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hVEGFA-TG Mice
Catalog Number：C001395
Strain Name：C57BL/6JCya-Tg(bRho-VEGFA)/Cya
Genetic Background：C57BL/6JCya
Reproduction：Carrier x WT
Strain Description
The Vascular Endothelial Growth Factor (VEGF) family is a group of highly specific endothelial growth factors intimately associated with angiogenesis. These factors promote increased vascular permeability, extracellular matrix degeneration, vascular endothelial cell migration and proliferation, and are capable of stimulating angiogenesis and increasing the permeability of existing vessels. As such, they play a pivotal role in normal vascular development and wound healing. The VEGF family comprises VEGFA, VEGFB, VEGFC, VEGFD, VEGFE, and PLGF [1]. Of these, VEGFA is the most commonly targeted in research related to neovascular ophthalmic diseases due to its crucial role in the proliferation, migration, and formation of endothelial cell microvessels [2]. Overexpression of VEGFA in the eye can result in abnormal vascular growth and leakage, leading to various ophthalmic diseases such as Age-Related Macular Degeneration (AMD), Diabetic Retinopathy (DR), and corneal neovascularization [2-3].
The hVEGFA-TG mouse is a transgenic model generated by Cyagen. In this model, the expression of human VEGFA CDS is driven by the bovine rhodopsin promoter, allowing for specific overexpression of the human VEGFA gene in the retina without affecting the expression of the endogenous VEGFA gene. This model exhibits clear retinal and choroidal vascular lesions while maintaining complete eye structure and can naturally develop diseases. Anti-VEGF drugs such as Aflibercept [4] have been evaluated for efficacy in this mouse model, demonstrating that Aflibercept can target and suppress VEGF expression, thereby alleviating retinal vascular lesions. As such, this model is well-suited for drug evaluation and mechanism research related to neovascular ophthalmic diseases.
Figure 1. Diagram of the gene editing strategy employed in the generation of hVEGFA-TG mice. Utilizing transgenic technology, the “Bovine rhodopsin promoter-Kozak-Human VEGFA CDS-Mouse Prm1 polyA” gene expression construct was successfully integrated into the mouse genome. This approach facilitated the specific overexpression of human VEGFA in the retina of hVEGFA-TG mice.
● Research on Age-Related Macular Degeneration (AMD);
● Research on Diabetic Retinopathy (DR);
● Research on corneal neovascular diseases.
1. Expression of human VEGFA and mouse VEGFA gene
Figure 2. Detection of human VEGFA and mouse VEGFA expression in B6J-hVEGFA-TG and WT mice. The qPCR analysis revealed that both human and mouse VEGFA genes were expressed in B6J-hVEGFA-TG mice. The expression level of mouse VEGFA was comparable to that in WT mice, indicating that the presence of human VEGFA did not affect mouse VEGFA expression.
2. Retinal morphology and retinal vasculature
Figure 3. Fundus morphology, OCT, and FFA results of WT and B6J-hVEGFA-TG mice. Compared with WT mice, the results of retinal OCT showed a slight structural disorder in the choroidal region of B6J-hVEGFA-TG mice. The ocular vessels of the mice were observed by FFA, the fundus of B6J-hVEGFA-TG mice showed vascular lesions as large fluorescein leakage compared with WT mice.
3. Electroretinogram (ERG)
Figure 4. Electroretinogram (ERG) detection results of WT and B6J-hVEGFA-TG mice. Compared with WT, the amplitudes of the a-wave and b-wave in both scotopic and photopic ERG recordings of B6J-hVEGFA-TG mice were nearly identical to those of the WT.
4. H&E staining and retinal FITC-Dextran perfusion
Figure 5. H&E staining and retinal FITC-dextran results of WT and B6J-hVEGFA-TG mice. Compared with WT mice, H&E staining revealed a pathological phenotype of vascular proliferation in the retinal area of B6J-hVEGFA-TG mice. After FITC-Dextran perfusion, retinal flat-mounts were prepared, showing abnormal vascular proliferation and structural disorganization in the retinas of B6J-hVEGFA-TG mice.
5. Retinal and choroidal isolectin GS-lB4 immunostaining
Figure 6. Immunostaining of retina, RPE and choroidal flat-mounts results of WT and B6J-hVEGFA-TG mice. IB4 staining of the retina, RPE and choroidal flat-mounts revealed abnormal blood vessel proliferation and structural disorder in the retina of B6J-hVEGFA-TG mice compared with WT mice, abnormal proliferation was also observed in the choroid area.
6. Pharmacodynamic evaluation of Aflibercept
Figure 7. Pharmacodynamic validation of VEGF-targeted drug/Aflibercept on B6J-hVEGFA-TG mice. Before Aflibercept injection, B6J-hVEGFA-TG mice exhibited obvious vascular lesions and large areas of fluorescein sodium leakage in the fundus. After Aflibercept injection, vascular lesions were significantly reduced and the area of eye lesions decreased. And with continued injections, ocular lesions gradually decreased until disappeared.
Route of administration: 3 μg/eye/week, intravitreal injection.
High-level expression of human VEGFA in hVEGFA-TG mice does not affect endogenous mouse VEGFA expression. This model exhibits retinal structural disorder, vascular proliferation, and large-area vascular leakage. Structural disorder and vascular proliferation are also present in the choroid. Aflibercept, an anti-VEGFA drug, can reduce vascular leakage and alleviates ocular vascular lesions in hVEGFA-TG mice.
In summary, hVEGFA-TG mice overexpress human VEGFA and naturally develop ocular retinal and choroidal lesions while maintaining intact eyeball structures. Anti-VEGFA drugs effectively alleviate ocular lesions. This model is suitable for drug evaluation and mechanism research of neovascular-related ophthalmic diseases.
References
[1] Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA. Vascular endothelial growth factor and angiogenesis. Pharmacol Rev. 2004 Dec;56(4):549-80.
[2] Apte RS, Chen DS, Ferrara N. VEGF in Signaling and Disease: Beyond Discovery and Development. Cell. 2019 Mar 7;176(6):1248-1264.
[3] Mesquita J, Castro-de-Sousa JP, Vaz-Pereira S, Neves A, Passarinha LA, Tomaz CT. Vascular endothelial growth factors and placenta growth factor in retinal vasculopathies: Current research and future perspectives. Cytokine Growth Factor Rev. 2018 Feb;39:102-115.
[4] Stewart MW, Grippon S, Kirkpatrick P. Aflibercept. Nat Rev Drug Discov. 2012 Mar 30;11(4):269-70.Hartong, D. T., Berson, E. L., & Dryja, T. P. (2006). Retinitis pigmentosa. The Lancet, 368(9549), 1795-1809.
