Abstract
Presentation Description :
Approximately half of patients treated with anti-vascular endothelial growth factor (anti-VEGF) are effectively treated for macular edema or proliferative diabetic retinopathy and many demonstrate improvement in visual function. However, there clearly remains opportunity for additional or improved treatment of retinal vascular permeability for patients with diabetic retinopathy. This presentation will review recent data demonstrating that genetically targeting the vascular endothelium with mutants of the tight junction protein occludin in order to prevent diabetes-induced retinal permeability also prevents loss of visual acuity in animal models of diabetes. Then, recent literature establishing Norrin and Wnt signaling associated with barriergenesis in the retina and brain will be discussed. The presentation will provide evidence that activation of the norrin signaling pathway effectively can restore barrier properties after VEGF signaling in endothelial cells and in vivo. Further, recent data exploring the role for a previously unrecognized contribution of a non-canonical signaling pathway will be provided. Specifically, norrin signaling inhibits the beta-catenin degradation complex and activates beta-catenin/TCF/LEF transcription through the canonical signaling pathway required for barrier formation. Disheveled (Dvl) acts as a branch point in norrin signaling contributing to both regulation of beta-catenin degradation and interacting directly with the tight junction proteins claudin 5 and ZO-1 through a novel, non-canonical signaling pathway. Data reveals that binding of Dvl1 to claudin 5 is necessary for junctional assembly and barrier properties since knockdown of Dvl1 or inhibition of Dvl1 and claudin 5 binding prevents norrin’s ability to induce barrier properties. Finally, results will be provided showing that norrin treatment of diabetic animals can prevent increased vascular permeability and loss of visual acuity showing that activation of the norrin signaling pathway may provide an alternative signaling pathway to treat diabetic retinopathy.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.