Systemically expressed soluble Tie2 inhibits intraocular neovascularization

Retinal and choroidal neovascularization are the most frequent causes of se vere and progressive vision loss. Studies have demonstrated that Tie2, an e ndothelial-specific receptor tyrosine kinase, plays a key role in angiogene sis. In this study, we determined whether adenovirus-mediated gene delivery of extracellular domain of the Tie2 receptor (ExTek) could inhibit experim ental retinal and choroidal neovascularization. Immunofluorescence histoche mistry with a monoclonal antibody to human Tie2 showed that Tie2 expression is prominent around and within the base of newly formed blood vessels of r etinal and choroidal neovascular lesions. A single intramuscular injection of adenovirus expressing ExTek genes achieved plasma levels of ExTek exceed ing 500 mug/ml in mice for 10 days (in neonates) and 7 days (in adults). Th is treatment inhibited retinal neovascularization by 47% (p< 0.05) in a mur ine model of ischemia-induced retinopathy. The same treatment reduced the i ncidence and extent of sodium fluorescein leakage from choroidal neovascula r lesions by 52% (p< 0.05) and 36% (p< 0.01), respectively, in a laser-indu ced murine choroidal neovascularization model. The same mice showed a 45% ( p< 0.001) reduction of integrated area of the choroidal neovascularization. These findings indicate that Tie2 signaling is a common component of the a ngiogenic pathway in both retinal and choroidal neovascularization, providi ng a potentially useful target in the treatment of intraocular neovascular diseases.