Vascular Endothelial Growth Factors In Eye Diseases Pathophysiology and New Therapeutic Strategies for Retinal and Choroideal Angiogenesis

Ocular neovascular diseases, including age related macular degeneration and diabetic retinopathy are major causes for blindness in the western world. The pathogenesis of these diseases remains partly unclear and currently there is no permanent cure for these diseases. In this study, we attempted to clarify the factors involved in the pathogenesis of diabetic retinopathy in type 1 and type 2 diabetes. We also experimentally evaluated the effects of overexpression of vascular endothelial growth factors (VEGF) -A and –D in the rabbit eye with adenovirus and baculovirus vectors. Finally, ocular phenotype of IGF-II/LDLR –/– ApoB 100/100 mouse was studied in order to develop a new animal model for age related eye diseases. Diabetic retinopathy in type 1 and type 2 diabetes showed a different pattern of growth factor expression, which may explain the differences seen in these states. In diabetic patients, in addition to VEGF-A also other growth factors, particularly angiopoietin 2 were abundantly present. VEGF-D seemed to be important especially in type 2 diabetic retinopathy. VEGF-A plays a major role in the pathogenesis of ocular neovascularization. Intravitreal injection of adenoviral VEGF-A165 into the rabbit eye led to breakdown of the blood-retina barrier and ultimately neovessel formation. Furthermore, blocking the action of VEGF-A165 prevented the progression of the angiogenic process. Intravitreal VEGF-D ∆N∆C in our experimental series with rabbits led to a similar breakdown of the blood retina barrier as VEGFA165 and increased permeability but it was not capable to induce neovessel formation alone. Administration of the therapeutic agent to the retina and choroidea can be difficult due to the tight barriers in the eye. Multiple injections into the eye may damage ocular structures and the risk of complications including endophthalmitis, cataract and haemorrhages increases. The optimal method for the delivery of therapeutic agents to the retina and choroidea has not yet been developed. Gene therapy offers an alternative in which the therapeutic protein or proteins are induced in the target tissue with a single injection for a prolonged time period. Eye is an ideal target for gene therapy because of its small size and tissue boundaries that prevent leakage of the therapeutic material to other tissues and systemic circulation. Viruses are widely used as vectors in gene transfer. In this study, intravitreal injection of adenovirus vector into the rabbit eye was efficient in delivering genes to the ganglion cell layer and inner retina. Baculoviruses showed transduction in the retinal pigment epithelium (RPE) and the photoreceptor layer even after the intravitreal injection into the rabbit eye. However, both vectors initiated an immune response in the target tissue, which limited the expression of the transducted gene to few weeks. Diabetic IGF-II/LDLR –/– ApoB 100/100 mice had moderately increased plasma glucose levels simulating early diabetes treated with diet therapy in humans. Aging transgenic mice showed changes especially in their retinal structures. Neovascularization was not seen in the retina. Instead, photoreceptor atrophy and dysregularities of normal retinal cell layers were found throughout the retina. This model might be useful for the evaluation of early diabetic changes and retinal degeneration. National Library of Medicine Classification: WW 270, WW 245, WK 835 Medical Subject Headings: Adenoviridae; Angiopoietins; Baculoviridae; Blood-Retinal Barrier; Choroidal Neovascularization; Diabetic Retinopathy; Disease Models, Animal; Eye/ blood supply; Gene Therapy; Gene Transfer Techniques; Neovascularization, Pathologic/ etiology; Retinal Degeneration; Retinal Neovascularization; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor D; Vascular Endothelial Growth Factors ”What was that? ”, asked Moomintroll, for a discovery (next to Mysterious Paths, Bathing, and Secrets) was what he liked most of all.