| Description |
Diabetic retinopathy is a neurovascular disease of the retina and is the leading cause of blindness in the working-age population in the United States. Complications as a result of hyperglycemia and diabetes mellitus (DM) break down the blood-retina barrier (BRB) and retinal vasculature. Current treatments have been shown to be ineffective in rescuing the damaged neurovasculature and often do not restore visual acuity. Endothelial cells line the vasculature in the circulatory system and are essential to maintain vascular integrity. These cells act as a highly selective permeable barrier between the lumen of the cardiovascular system and surrounding tissues, allowing certain materials to pass in and out of the bloodstream. Hyperglycemia compromises the endothelium and creates vascular leakage, which advances diabetic retinopathy and can lead to vision loss if left untreated. The purpose of this project was to ultimately test whether or not COMP-Ang1, a novel molecule designed to mirror the native Angiopoietin 1 protein, can prevent and/or rescue the compromised integrity of the cardiovascular endothelium. The effects of COMP-Ang1 on HRMVECs were determined using ECIS and Western blots. Here we show that COMP-Ang1 increased barrier resistance compared to Ang1 and PBS in HRMVECs and VEGF decreased barrier resistance compared to PBS, even in the presence of COMPAng1. Western blots showed COMP-Ang1 decreased Src phosphorylation and increased VE-cadherin compared to cells treated with PBS. VEGF increased Src phosphorylation and decreased VE-cadherin compared to PBS. All Western blot samples showed equal amounts of GAPDH, demonstrating that sample sizes were consistent between experiments. This study also shows that COMP-Ang1 was able to reverse structural damage caused by diabetic retinopathy in the Ins2Akita mouse model simulating Type 1 diabetes. Based on these results, we conclude that COMP-Ang1 promotes endothelial barrier integrity and increases VE-cadherin stabilization while decreasing Src phosphorylation. Because barrier integrity and VE-cadherin are compromised in diabetic retinopathy and lead to vascular leakage and other harmful pathologies, COMP-Ang1 could serve as a therapeutic agent when treating diabetic retinopathy and other diseases that compromise vascular integrity. |
