title: Systemically expressed soluble Tie2 inhibits intraocular neovascularization.
abstract: Retinal and choroidal neovascularization are the most frequent causes of severe and progressive vision loss. Studies have demonstrated that Tie2, an endothelial-specific receptor tyrosine kinase, plays a key role in angiogenesis. In this study, we determined whether adenovirus-mediated gene delivery of extracellular domain of the Tie2 receptor (ExTek) could inhibit experimental retinal and choroidal neovascularization. Immunofluorescence histochemistry with a monoclonal antibody to human Tie2 showed that Tie2 expression is prominent around and within the base of newly formed blood vessels of retinal and choroidal neovascular lesions. A single intramuscular injection of adenovirus expressing ExTek genes achieved plasma levels of ExTek exceeding 500 microg/ml in mice for 10 days (in neonates) and 7 days (in adults). This treatment inhibited retinal neovascularization by 47% (p < 0.05) in a murine model of ischemia-induced retinopathy. The same treatment reduced the incidence and extent of sodium fluorescein leakage from choroidal neovascular lesions by 52% (p < 0.05) and 36% (p < 0.01), respectively, in a laser-induced 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 angiogenic pathway in both retinal and choroidal neovascularization, providing a potentially useful target in the treatment of intraocular neovascular diseases.
authors: Department of Ophthalmology, Keck School of Medicine at the University of Southern California, 2011 Zonal Avenue, Los Angeles, CA 90033, USA.
authors: M
authors: M
authors: Hangai
authors: Y S
authors: YS
authors: Moon
authors: N
authors: N
authors: Kitaya
authors: C K
authors: CK
authors: Chan
authors: D Y
authors: DY
authors: Wu
authors: K G
authors: KG
authors: Peters
authors: S J
authors: SJ
authors: Ryan
authors: D R
authors: DR
authors: Hinton
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000367:Age Factors; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002829:Choroid / Q000098:blood supply*; D019793:Fluorescein / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D007511:Ischemia; D051379:Mice; D008856:Microscopy, Fluorescence; D009363:Neoplasm Proteins / Q000097:blood / Q000737:chemistry / Q000235:genetics*; D009389:Neovascularization, Pathologic; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins; D042787:Receptor, TIE-2; D012171:Retinal Vessels / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D020533:Angiogenesis Inhibitors; C105373:MEN1 protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D042787:Receptor, TIE-2; D019793:Fluorescein