Purchase this article with an account.
Judd M. Cahoon, Hiro Uehara, Ling Luo, Thomas Olsen, Anthony Radosevich, Yang K. Cho, Jacquelyn M. Simonis, Bonnie Archer, Bala Ambati; CompAng1 Increases VE-cadherin Stability, Decreases Vascular Leakage and Increases Soluble VEGF Receptor 1 in the Diabetic Mouse Retina. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2099.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Diabetes Mellitus, a metabolic disease affecting nearly eight percent of the United States population, is the leading cause of new blindness among adults aged 20-74 years. The pathology behind diabetic retinopathy most likely involves vascular leakage. The angiopoietin ligands 1 and 2 acting on the Tie2 receptor are known to be important in vasculature leakage. In our study we used the Ins2 Akita mouse as an animal model of diabetes and used a stable, soluble form of angiopoietin 1 called CompAng1 expressed via adeno-associated virus (AAV2_CompAng1) in the retina of Akita mice to determine whether CompAng1 can reduce diabetic vascular hyperpermeability.
One month following intravitreal injection of AAV2_CompAng1 or control AAV2.AcGFP into diabetic Akita mice we assessed levels of CompAng1 in the retina by Western blot as well its effect on vascular leakage by Evans blue assay. Alpha-SMA staining was used to assess effect on pericytes, while VE-cadherin, VEGF and VEGF receptor expression were assessed by Western blotting and RT-PCR.
AAV2_CompAng1 induced retinal CompAng-1 expression and reduced vascular permeability in diabetic Akita mice to levels comparable to wild-type C57Bl/6 mice. We did not find any changes in pericyte number but did find an increase in vessel area in those mice treated with AAV2_CompAng1(30.5% increase over control) in the absence of neovascularization. AAV2_CompAng1 increased VE-cadherin protein but not mRNA expression. Although no difference was found in VEFG receptor 2 and VEGF-A expression between AAV2_CompAng1 and control, we did observe an increase in soluble VEGF receptor 1 expression in mice treated with AAV2_CompAng1 compared to control. To elucidate the relationship between AAV2_CompAng1 and soluble VEGF receptor 1 we assessed Ets-1, a transcription factor whose binding sequence is present in the VEGF receptor 1 promoter as well as whose expression is stimulated by the Tie2-Angiopoietin 1 signaling cascade. Ets-1 mRNA was increased 2.5-fold over control by AAV2_CompAng1.
AAV2_CompAng1 increases VE-cadherin protein stability through the up-regulation of soluble VEGF receptor 1, which is known to sequester VEGF-A preventing it from signaling the degradation of VE-cadherin. Ets-1 may have an important role in this process. Thus, AAV2-CompAng1 may be increasing the stability of VE-cadherin protein without increasing its transcription.
This PDF is available to Subscribers Only