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Judd M. Cahoon, Hironori Uehara, Ling Luo, Thomas K. Olsen, Tadashi R. Miya, Vainu'Upo R. Jessop, Bonnie J. Archer, Bala K. Ambati; COMPAng1 Prevents Decreases in Visual Acuity and Retinal Thinning in the Diabetic Mouse. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5758.
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Vascular dysfunction plays a role in many pathologies. Normalizing the vasculature is a potential mechanism to combat deficiencies induced by a failing vascular tree. Diabetic macular edema resulting from vascular hyperpermeability is the leading cause of vision loss in working-age Americans. Angiopoietin-1 plays a critical role in the development of macular edema due to its effects on vascular permeability. Here, we treat diabetic mice with a stable soluble variant of angiopoietin 1, COMP-Ang1, to mitigate vascular leakage and the hallmarks of ischemia associated with diabetes.
Diabetic mice (type 1 diabetic Akita Ins2+/-, type 2 diabetic db/db) were treated at 2 months of age with one intravitreal injection of an adeno associated virus expressing COMPAng1, AcGFP, or phosphate buffered saline as control. Hallmarks of ischemic retinopathy were assessed over the next four months including retinal thickness (as measured by optical coherence tomography) visual acuity (as measured by OptoMotry), as well as vessel area (as observed using immunohistochemistry), vascular hyperpermeability (as assessed by Evans blue dye), and protein expression (as assessed by Western blot).
COMPAng1 prevented diabetes-induced decreases in retinal ganglion cell layer thickness (14.9 +/- 3.1 um treated vs. 8.1 +/- 1.7 um control, p < 0.05) and visual acuity (0.307 +/- 0.08 cycles/degree treated vs. 0.11 +/- 0.11 control, p < 0.05). Vascular area was returned to non-diabetic control levels (21% vs. 16% vessel area (isolectin positive)/total area p 0.05). Furthermore, COMP-Ang1 treatment increased VE-cadherin stability and decreased VEGF-A expression. Vascular hyperpermeability was reduced in COMPAng1 treated diabetic mice compared to control (.0020 +/- 0.0008 vs. 0.0072 +/- 0.0004 absorbance, p < 0.05).
We propose that COMP-Ang1 not only directly prevents vascular leak by stabilizing VE-cadherin but the normalized vasculature also adequately perfuses tissue resulting in less hypoxia-driven VEGF secretion. COMP-Ang1 promotes vascular integrity, prevents retinal ischemia, and decreases vascular permeability through suppression of VEGF-A expression and could be useful in the treatment of non-proliferative diabetic retinopathy.
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