Schlüter Annabelle, Aksan Bahar, Diem Ricarda, Fairless Richard, Mauceri Daniela
Department of Neurobiology, Interdisciplinary Center for Neurosciences, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
Department of Neurology, University Clinic Heidelberg, Im Neuenheimer Feld 368, 69120 Heidelberg, Germany.
Mol Ther Methods Clin Dev. 2019 Dec 25;17:281-299. doi: 10.1016/j.omtm.2019.12.009. eCollection 2020 Jun 12.
In the central nervous system, neurons and the vasculature influence each other. While it is well described that a functional vascular system is trophic to neurons and that vascular damage contributes to neurodegeneration, the opposite scenario in which neural damage might impact the microvasculature is less defined. In this study, using an excitotoxic approach in adult mice as a tool to cause specific damage to retinal ganglion cells, we detected subsequent damage to endothelial cells in retinal capillaries. Furthermore, we detected decreased expression of vascular endothelial growth factor D (VEGFD) in retinal ganglion cells. VEGFD supplementation via neuronal-specific viral-mediated expression or acute intravitreal delivery of the mature protein preserved the structural and functional integrity of retinal ganglion cells against excitotoxicity and, additionally, spared endothelial cells from degeneration. Viral-mediated suppression of expression of the VEGFD-binding receptor VEGFR3 in retinal ganglion cells revealed that VEGFD exerts its protective capacity directly on retinal ganglion cells, while protection of endothelial cells is the result of upheld neuronal integrity. These findings suggest that VEGFD supplementation might be a novel, clinically applicable approach for neuronal and vascular protection.
在中枢神经系统中，神经元和脉管系统相互影响。虽然已有充分描述表明功能性脉管系统对神经元具有营养作用，且血管损伤会导致神经退行性变，但神经损伤可能影响微血管系统的相反情况却较少被明确。在本研究中，我们使用成年小鼠的兴奋性毒性方法作为对视网膜神经节细胞造成特异性损伤的工具，检测到视网膜毛细血管内皮细胞随后发生的损伤。此外，我们检测到视网膜神经节细胞中血管内皮生长因子D（VEGFD）的表达降低。通过神经元特异性病毒介导的表达或成熟蛋白的急性玻璃体内递送补充VEGFD，可保护视网膜神经节细胞的结构和功能完整性免受兴奋性毒性影响，此外，还可使内皮细胞免于退化。病毒介导的视网膜神经节细胞中VEGFD结合受体VEGFR3表达的抑制表明，VEGFD直接对视网膜神经节细胞发挥其保护作用，而对内皮细胞的保护是维持神经元完整性的结果。这些发现表明，补充VEGFD可能是一种新的、可临床应用的神经元和血管保护方法。
