Abstract
Abstract: :
Purpose: To determine the role of angiopoietin 2 (Ang 2) in the regulation of proteinase expression during angiogenesis, and whether inhibition of Ang 2 signaling can suppress the extent of retinal neovascularization (NV) in a well-established animal model. Methods: Bovine retinal microvascular endothelial cells (BRMVEC) were established in culture and treated for 16 hours with increasing concentrations of Ang 2 (0, 1 and 10 ng/ml) and examined for the production of proteinases. Retinal NV was induced by exposing mice to 75% oxygen on postnatal days 7-12 followed by exposure to room air on days 12-17. The effects of inhibiting Ang 2 binding to the Tie-2 (Tek) receptor and its effect on the development of retinal NV were studied in this animal model. Animals were treated with an intraperitoneal injection of the Tie-2 antagonist, Tek delta Fc (Immunex Corporation, Seattle, WA) at a dose of 250 ug per animal once a day on days 12-16. Control animals included oxygen exposed mice receiving an intraperitoneal injection of 250 ug of murine IgG on days 12-16. Results: Ang 2 stimulation of cultured BRMVEC resulted in an increase in both MMP2 and MMP9 expression. Histological analysis of mice treated with Tek delta Fc showed significant inhibition of retinal neovascularization (56%). Conclusion: The upregulation of proteinases in microvascular endothelial cells by Ang2 may be an important early response during the development of retinal neovascularization. Furthermore, inhibition of the activity of this growth factor in the eye suppresses retinal NV possibly through a reduction in the expression of proteinases necessary for cell migration during angiogenesis.
Keywords: 566 retinal neovascularization • 614 vascular cells • 316 animal model