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Intraocular expression of endostatin reduces VEGF-induced retinal vascular permeability, neovascularization, and
Kyoichi Takahashi1, Yoshitsugu Saishin, Yumiko Saishin
1Department of Ophthalmology, The Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, Maryland 21287-9277, USA.
Abstract:
Endostatin, a proteolytic fragment of collagen XVIII, is an endogenous inhibitor of tumor angiogenesis that also inhibits choroidal neovascularization. In this study, we assessed the effects of increased intraocular expression of endostatin on vascular endothelial growth factor (VEGF)-induced changes in the retina. After subretinal injection of a pair of gutless adenoviral vectors (AGV) designed to provide tamoxifen-inducible expression of endostatin, diffuse endostatin immunoreactivity was induced thoroughout the retina by administration of tamoxifen. Induction of endostatin in double transgenic mice with doxycycline-induced expression of VEGF in the retina resulted in significant suppression of leakage of intravascular [3H]mannitol into the retina. The ability of endostatin to reduce VEGF-induced retinal vascular permeability was confirmed by using [3H]mannitol leakage and two other parameters, fluorescein leakage and retinal thickness, after subretinal injection of a bovine immunodeficiency lentiviral vector coding for endostatin (BIV-vectored endostatin, or BIVendostatin). Subretinal injection of BIVendostatin resulted in more discrete, less intense staining for endostatin in the retina than that seen with the inducible AGV system, which suggested lower levels and allowed visualization of sites where endostatin was concentrated. Endostatin staining outlined retinal blood vessels, which suggested endostatin binding to a component of vessel walls. More prolonged or higher level expression of VEGF in the retina resulted in neovascularization and retinal detachment, both of which were also significantly reduced by BIVendostatin. These data suggest that endostatin may be an endogenous inhibitor of vasopermeability as well as neovascularization. In patients with diabetic retinopathy, endostatin gene transfer may provide a way to decrease the risk of three causes of visual loss: macular edema, neovascularization, and retinal detachment.
Insights
Endostatin, an inhibitor of blood vessel growth, was found to significantly reduce retinal vascular leakage and neovascularization caused by VEGF. This suggests potential for gene therapy in treating diabetic retinopathy and preventing vision loss.
Area of Science:
- Ophthalmology
- Molecular Biology
- Angiogenesis Research
Background:
- Endostatin is a known inhibitor of tumor angiogenesis and choroidal neovascularization.
- Vascular Endothelial Growth Factor (VEGF) plays a critical role in retinal vascular diseases.
Purpose of the Study:
- To investigate the effects of intraocular endostatin expression on VEGF-induced retinal changes.
- To evaluate endostatin's potential as a therapeutic agent for retinal vascular disorders.
Main Methods:
- Subretinal injection of adenoviral vectors for tamoxifen-inducible endostatin expression.
- Utilized [3H]mannitol leakage, fluorescein leakage, and retinal thickness measurements to assess vascular permeability.
- Employed bovine immunodeficiency lentiviral vectors for endostatin gene transfer (BIVendostatin).
Main Results:
- Endostatin induction significantly suppressed VEGF-induced leakage of [3H]mannitol into the retina.
- BIVendostatin reduced retinal vascular permeability, neovascularization, and retinal detachment.
- Endostatin staining suggested binding to retinal blood vessel walls.
Conclusions:
- Endostatin acts as an endogenous inhibitor of retinal vasopermeability and neovascularization.
- Endostatin gene transfer holds promise for treating diabetic retinopathy, reducing risks of macular edema, neovascularization, and detachment.