Inhibition of Angiogenesis by Adenovirus-Mediated sFlt-1 Expression in a Rat Model of Corneal Neovascularization
- 1 July 2001
- journal article
- research article
- Published by Mary Ann Liebert Inc in Human Gene Therapy
- Vol. 12 (10) , 1299-1310
- https://doi.org/10.1089/104303401750270959
Abstract
Pathological angiogenesis, or the production of new capillary vessels from preexisting vasculature, within the eye is a serious event that often leads to blindness. Upregulation of vascular endothelial growth factor (VEGF) has been linked to neovascularization in the eye, suggesting that it could be a suitable target to inhibit angiogenic changes. This work investigated whether the presence of a proven antiangiogenic factor, the soluble variant of the VEGF receptor, sFlt-1, in the anterior chamber is sufficient to inhibit new vessel formation in the cornea in an animal model of corneal neovascularization. A recombinant adenovirus vector that can mediate efficient in vivo gene transfer and expression in ocular cells was selected as a delivery agent. We have shown that after the injection of Ad.βgal into the anterior chamber of normal and cauterized rat eyes, corneal endothelial cells and cells of the trabecular meshwork were efficiently transduced and that β-galactosidase (β-Gal) expression was maintained up to 10 days postinjection. Cauterization significantly increased the amount of immunoreactive VEGF in vehicle- or Ad.null-injected animals (t test, p < 0.001 and p < 0.001, respectively). However, when cauterization was combined with Ad.sflt injection there was no statistically significant increase in the amount of immunoreactive VEGF (p = 0.12). The injection of Ad.sflt into the anterior chamber slowed or inhibited VEGF-induced angiogenic changes. After cauterization, 100% of uninjected and vehicle-injected and 82% of Ad.null-injected animals developed moderate to severe corneal angiogenesis in contrast to 18% of Ad.sflt-injected animals. These in vivo results suggest that the transient presence of antiangiogenic agents in the anterior chamber can be successfully used to inhibit the development of corneal angiogenesis.Keywords
This publication has 38 references indexed in Scilit:
- Evaluation of Adeno-Associated Virus-Mediated Gene Transfer into the Rat Retina by Clinical Fluorescence PhotographyHuman Gene Therapy, 1999
- Expression of cell adhesion molecules and vascular endothelial growth factor in experimental choroidal neovascularisation in the ratBritish Journal of Ophthalmology, 1998
- Regional Suppression of Tumor Growth byIn VivoTransfer of a cDNA Encoding a Secreted Form of the Extracellular Domain of theflt-1Vascular Endothelial Growth Factor ReceptorHuman Gene Therapy, 1998
- Identification of a Natural Soluble Form of the Vascular Endothelial Growth Factor Receptor, FLT-1, and Its Heterodimerization with KDRBiochemical and Biophysical Research Communications, 1996
- Levels of vascular endothelial growth factor are elevated in the vitreous of patients with subretinal neovascularisation.British Journal of Ophthalmology, 1996
- Vascular Endothelial Growth Factor, a Potent and Selective Angiogenic AgentJournal of Biological Chemistry, 1996
- Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor.Proceedings of the National Academy of Sciences, 1993
- Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivoNature, 1993
- Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factorBiochemical and Biophysical Research Communications, 1992
- The fms -Like Tyrosine Kinase, a Receptor for Vascular Endothelial Growth FactorScience, 1992