VEGFD signaling: coupling of neuronal function with the CNS vascular system

• Applicant: Professorin Dr. Daniela Mauceri
• Subject Area: Ophthalmology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 269353708

Neurons and the vasculature influence each other during both development and maintenance of different regions of the central nervous system (CNS). In the retina, a tight structural and functional coupling between retinal ganglion cells (RGCs) and capillaries exists. RGCs are the neurons transmitting visual information to the brain and their death is accompanied by devastating effects on vision. In experimental models of neural retinal damage, degeneration of the capillaries after RGCs death has been observed. However, the molecular and cellular mechanisms by which RGCs degeneration impact on the retinal microvasculature are vastly not known. One of the mechanisms contributing to RGCs loss is excitotoxicity. NMDAR receptors (NMDARs) are the principal initiators of excitotoxic cell death induced either by high glutamate levels or NMDA exposure. Synaptic NMDARs lead to synaptic plasticity and neuroprotection as they upregulate pro-survival genes and downregulate pro-death genes while extrasynaptic NMDARs cause cell death. The key effector in the modulation of NMDARs-governed gene transcription is calcium. Nuclear calcium signaling regulates gene expression by modulating the activity of transcription factors and by regulating epigenetic processes, such as nucleo-cytoplasmic shuttling of histone deacetylates (HDACs). Vascular Endothelial Growth Factor D (VEGFD) belongs to the VEGF protein family and is known for its angiogenic and lymphangiogenic properties. We identified VEGFD as a regulator of neuronal morphology and cognitive abilities in the adult mouse brain. Recently, we observed that NMDA-induced excitotoxicity causes a dramatic reduction in neuronal VEGFD expression accompanied by dendritic damage, which can be blocked by VEGFD administration. We hypothesise that in the adult retina, excitotoxicity, caused by activation of extrasynaptic NMDARs, promotes nuclear accumulation of HDACs and reduction of VEGFD expression. These events influence dendritic architecture and survival of RGC, which, in turn, affects capillary integrity. We will use an in vivo mouse model of RGC degeneration to characterise changes in RGC dendritic architecture, HDACs activation and VEGFD expression. In parallel, we will analyse the influence of RGC loss and HDACs activation on the retina microvasculature. Finally, we will investigate the therapeutic potential of VEGFD in protecting both RGC and capillaries from injury.

• DFG Programme: Research Units
• Subproject of: FOR 2325: Interactions at the Neurovascular Interface
• Co-Investigator: Professor Dr. Hilmar Bading