Suppression of Diabetic Retinopathy with Angiopoietin-1

Abstract

Diabetic retinopathy remains a leading cause of irreversible blindness. A critical early pathology in the disease is the adhesion of leukocytes to the retinal vasculature, a process that occurs, in part, via intercellular adhesion molecule-1. Once leukocyte adhesion occurs, endothelial cell injury ensues, as does blood-retinal barrier breakdown. Here we show that angiopoietin-1 can prevent and reverse these diabetic retinal vascular changes in both new and established diabetes. Angiopoietin-1, when given intravitreally to newly diabetic rats, normalized retinal vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 mRNA and protein levels, leading to reductions in leukocyte adhesion, endothelial cell injury, and blood-retinal barrier breakdown. When an adenovirus coding for angiopoietin-1 was given systemically to mice with established diabetes, it similarly inhibited leukocyte adhesion and endothelial cell injury and blood-retinal barrier breakdown. These changes coincided with reductions in retinal eNOS, nitric oxide, Akt (protein kinase B), and MAP kinase activity, known mediators of VEGF bioactivity and leukocyte adhesion. When endogenous VEGF bioactivity was inhibited with a soluble Flt-1/Fc chimera, retinal Akt kinase activity was significantly reduced in vivo. Taken together, these data document new vascular and anti-inflammatory bioactivities for angiopoietin-1 and identify it as the first naturally occurring protein that directly protects the retinal vasculature in diabetes.

Strengthening tight junctions of retinal microvascular endothelial cells by pericytes under normoxia and hypoxia involving angiopoietin-1 signal way

“…26 Our data showed that Ang-1 neutralizing antibody pretreatment prominently blocked PCM's TJ-strengthening effect through downregulating occludin. As reported previously, Ang-1, derived from pericytes, performed its total effects through Tie2 receptor on ECs.…”

Angiogenic Actions of Angiopoietin-1 Require Endothelium-Derived Nitric Oxide

“…Pharmacological inhibitors of PI3-kinase and NOS blocked Ang1-induced NO release and prevented EC capillarylike network formation; therefore, signaling between Tie2 and PI3-kinase appears to be essential for Ang1-induced angiogenesis in vitro. This is in apparent conflict with the effects of Ang1 in a rodent model of diabetic retinopathy, 54 in which the diabetes-induced increases in retinal eNOS and NO levels were reduced by Ang1. However, this may have been a result of indirect anti-inflammatory effects of Ang1 in this model, outweighing the direct actions of Ang-1 on these pathways.…”

“…However, this may have been a result of indirect anti-inflammatory effects of Ang1 in this model, outweighing the direct actions of Ang-1 on these pathways. 54 The role of endothelium-derived NO in Ang1-induced neovascularization was confirmed in vivo using eNOS KO mice. Although the in vitro angiogenesis models are useful in exploring the mechanisms underlying this complex process, they may not reproduce faithfully all of the events of the angiogenic cascade required for new blood vessel formation in vivo.…”

Angiopoietin 1 inhibits ocular neovascularization and breakdown of the blood–retinal barrier

“…26 It is not clear that breakdown of the blood-retinal barrier occurring days after the onset of hyperglycemia has anything to do with diabetic retinopathy, which requires years of hyperglycemia to develop, but its suppression by Ang1 shows another situation in which Ang1 exhibits antipermeability effects in the eye. The above-mentioned study 26 did not examine the effect of Ang1 on ocular neovascularization, and to our knowledge the present study is the first demonstration that Ang1 suppresses ocular neovascularization.…”