Analysis of VE-Cadherin Y685 phosphorylation in HBP activation-induced breakdown of the NVU in the retina using novel knockout mice

• Applicant: Privatdozentin Dr. Yuxi Feng
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 511337830

The Neurovascular Unit (NVU) exists in the brain as well as in the retina. Breakdown of the NVU can occur in a variety of ocular disorders such as diabetic retinopathy, retinopathy of prematurity, and retinal degenerative diseases. The destabilization of the NVU in diabetic retinopathy is attributed to chronic hyperglycemia, along with the alteration of associated biochemical pathways, in particular the activation of hexosamine biosynthetic pathway (HBP). The end product of the HBP, UDP-N-acetylglucosamine, modifies a plethora of proteins, resulting in the alteration of their functions. Subsequent dysregulation of growth factors including Angiopoietin-2 and VEGF correlates with the breakdown of the NVU, leading to vascular hyperpermeability, pericyte and endothelial cell loss, and/or angiogenesis. Retinal vascular permeability is predominantly controlled by adherens junctions between endothelial cells, which are mainly comprised of VE-Cadherin. Published data from us and others, and our preliminary data show that membrane VE-Cadherin and its phosphorylation at site Y685 are associated with the breakdown of the NVU upon activation of the HBP in diabetic retinopathy and in NDPK B deficient retinas that mimic the pathology of diabetic retinopathy in the absence of hyperglycemia. However, the role of VE-Cadherin and its phosphorylation site at Y685 in HBP activation-induced NVU breakdown is still not clear. This proposal therefore aims to investigate the involvement and the underlying mechanisms of VE-Cadherin Y685 phosphorylation in the breakdown of the NVU by subjecting VE-Cadherin Y685F mutant mice in vivo to hyperglycemia or NDPK B deficiency, as well as hypoxia-induced retinopathy. In vitro studies using cultured endothelial cells with gene manipulation strategies will clarify the underlying mechanisms.

• DFG Programme: Research Grants