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Aki Kato, Tsutomu Yasukawa, Kon-ichi Arai, Ayae Kubota, Yuichiro Ogura; Tissue Plasminogen Activator As An Anti-angiogenic Agent. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2961.
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Anti-vascular endothelial growth factor (VEGF) drugs such as ranibizumab has been effectively utilized in the treatment of age-related macular degeneration. However, once-developed fibrovascular tissues often remain in the subretinal space and mechanically damage the retina. Tissue plasminogen activator (tPA) is a fibrinolytic compound, utilized originally to treat embolic or thrombotic stroke and as an adjuvant for displacement of submacular hemorrhage. The purpose of this study is to investigate possible complimentary anti-angiogenic effects of tPA.
Human umbilical vein endothelial cells (HUVECs) were cultured and seeded onto collagen I-coated 96-well culture plates at a density of 3x103 cells/well. On the following day, tPA was added to the medium at various concentrations. After 24 h after incubation, cell growth was assessed by using XTT assay. A basic fibroblast growth factor (bFGF)-impregnated gelatin hydrogel sheet was implanted into a corneal pocket in rabbits to induce corneal neovascularization. Then intravitreal injection of tPA (4x104 IU/100 µl) (n=6) or saline as a control (n=4) was performed. The maximal length of induced corneal neovascularization was measured at 1, 2 and 4 week.
Neither growth nor viability of HUVECs was affected by tPA at concentrations of 5x105 IU/ml or lower. In a rabbit corneal neovascularization model, limbal injections were followed by sprouting of new vessels from the limbus toward bFGF-impregnated hydrogel. The mean length of new vessels was 1.0±0.4 mm at week 1, 1.6±0.7 mm at week 2, and 3.1±1.9 mm at week 4 in control eyes. In contrast, neovascularization was highly suppressed in eyes with intravitreal tPA. The mean length of new vessels was 0.17±0.4 mm at week 1, 0±0 mm at week 2, and 0±0 mm at week 4.
In vitro experiment showed that tPA did not affect the growth and viability of endothelial cells. Nevertheless, tPA remarkably suppressed the development of neovascularization in a rabbit corneal neovascularization model. These findings suggested that fibrin might be essential for angiogenesis and that tPA might be a possible adjuvant in the treatment of ocular angiogenesis itself as well as submacular hemorrhage.
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