VEGFD Protects Retinal Ganglion Cells and, consequently, Capillaries against Excitotoxic Injury

Schlüter, Annabelle; Aksan, Bahar; Diem, Ricarda; Fairless, Richard; Mauceri, Daniela

doi:10.1016/j.omtm.2019.12.009

Cited by 15 publications

(8 citation statements)

References 93 publications

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“…These molecules are described to have dual effects by enhancing either protective or detrimental pathways. For instance, VEGF release, particularly the isoform VEGFA [ 179 , 180 ], in combination with reactive oxygen species (ROS) production in diabetic retinopathy has been shown to enhance retinal degeneration [ 181 ], whereas VEGFD is protective for RGCs and the retinal vasculature [ 182 ]. In addition, the secretion of TNF-α has been shown to exert early neuroprotective effects [ 183 ] but to ultimately induce Müller cell gliosis and RGC death in the glaucomatous retina [ 184 ].…”

Section: Glutamate Excitotoxicity In the Retinamentioning

confidence: 99%

Retinal Glutamate Neurotransmission: From Physiology to Pathophysiological Mechanisms of Retinal Ganglion Cell Degeneration

Boccuni

Fairless

2022

Life

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Glutamate neurotransmission and metabolism are finely modulated by the retinal network, where the efficient processing of visual information is shaped by the differential distribution and composition of glutamate receptors and transporters. However, disturbances in glutamate homeostasis can result in glutamate excitotoxicity, a major initiating factor of common neurodegenerative diseases. Within the retina, glutamate excitotoxicity can impair visual transmission by initiating degeneration of neuronal populations, including retinal ganglion cells (RGCs). The vulnerability of RGCs is observed not just as a result of retinal diseases but has also been ascribed to other common neurodegenerative and peripheral diseases. In this review, we describe the vulnerability of RGCs to glutamate excitotoxicity and the contribution of different glutamate receptors and transporters to this. In particular, we focus on the N-methyl-d-aspartate (NMDA) receptor as the major effector of glutamate-induced mechanisms of neurodegeneration, including impairment of calcium homeostasis, changes in gene expression and signalling, and mitochondrial dysfunction, as well as the role of endoplasmic reticular stress. Due to recent developments in the search for modulators of NMDA receptor signalling, novel neuroprotective strategies may be on the horizon.

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Section: Glutamate Excitotoxicity In the Retinamentioning

confidence: 99%

Retinal Glutamate Neurotransmission: From Physiology to Pathophysiological Mechanisms of Retinal Ganglion Cell Degeneration

Boccuni

Fairless

2022

Life

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“…Notably, elevated VEGF-C and VEGF-D levels were found in the retinal pigment epithelium (RPE) of patients with age-related macular degeneration (Vellanki et al, 2016). There are also data confirming a significant role of VEGF-D in retinal angiogenesis and ganglion cell protection under excitotoxic injury (Schlüter et al, 2020). In addition, it was demonstrated that hypoxia-induced expression of VEGF-C in the retina is as potent as VEGF-A in inducing pathological retinal neovascularization in PDR and retinopathy of prematurity (Campochiaro, 2015;Singh et al, 2015;Vellanki et al, 2016).…”

Section: Discussionmentioning

confidence: 91%

Starvation to Glucose Reprograms Development of Neurovascular Unit in Embryonic Retinal Cells

Özgümüş

Сулаєва

Jain

et al. 2021

Front. Cell Dev. Biol.

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Perinatal exposure to starvation is a risk factor for development of severe retinopathy in adult patients with diabetes. However, the underlying mechanisms are not completely understood. In the present study, we shed light on molecular consequences of exposure to short-time glucose starvation on the transcriptome profile of mouse embryonic retinal cells. We found a profound downregulation of genes regulating development of retinal neurons, which was accompanied by reduced expression of genes encoding for glycolytic enzymes and glutamatergic signaling. At the same time, glial and vascular markers were upregulated, mimicking the diabetes-associated increase of angiogenesis—a hallmark of pathogenic features in diabetic retinopathy. Energy deprivation as a consequence of starvation to glucose seems to be compensated by upregulation of genes involved in fatty acid elongation. Results from the present study demonstrate that short-term glucose deprivation during early fetal life differentially alters expression of metabolism- and function-related genes and could have detrimental and lasting effects on gene expression in the retinal neurons, glial cells, and vascular elements and thus potentially disrupting gene regulatory networks essential for the formation of the retinal neurovascular unit. Abnormal developmental programming during retinogenesis may serve as a trigger of reactive gliosis, accelerated neurodegeneration, and increased vascularization, which may promote development of severe retinopathy in patients with diabetes later in life.

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“…These findings suggest that VEGF-D supplementation might be a novel, clinically applicable approach for neuronal and vascular protection [11]. However, the study by potentially explain that such effect is due to increased protection and vascular integrity [11], moreover, Schluter shows that VEGF-D has a positive effect on neuronal integrity [11].…”

Section: Discussionmentioning

confidence: 99%

“…Schluter et al [11] showed on mice model that in vivo VEGF-D supplementation via preserved the structural and functional integrity of retinal ganglion cells agains texcito toxicity and, additionally spared endothelial cells from degeneration [11]. Viral-mediated suppression of expression of the VEGF-D-binding receptor VEGFR3 in retinal ganglion cells revealed that VEGF-D exerts its protective capacity directly on retinal ganglion cells, while protection of endothelial cells is the result of upheld neuronalintegrity [11]. These findings suggest that VEGF-D supplementation might be a novel, clinically applicable approach for neuronal and vascular protection [11].…”

Section: Discussionmentioning

confidence: 99%

“…Viral-mediated suppression of expression of the VEGF-D-binding receptor VEGFR3 in retinal ganglion cells revealed that VEGF-D exerts its protective capacity directly on retinal ganglion cells, while protection of endothelial cells is the result of upheld neuronalintegrity [11]. These findings suggest that VEGF-D supplementation might be a novel, clinically applicable approach for neuronal and vascular protection [11]. However, the study by potentially explain that such effect is due to increased protection and vascular integrity [11], moreover, Schluter shows that VEGF-D has a positive effect on neuronal integrity [11].…”

Section: Discussionmentioning

confidence: 99%

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The Different Impact of VEGF-A and VEGF-D on Peritumoral Brain Edema

Siedlecki¹

2020

BJSTR

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The study consisted of VEGF-A and VEGF-D levels analysis in the blood samples in patients with brain tumors. VEGF is a family of angiogenic factors. This study evaluated the association between VEGF-A and VEGF-D levels and the extent of peritumoral brain edema. The study group was divided into patients with moderate and severe edema based on the Stenih off scale and its modification for posterior foss a tumors. It was found that plasma VEGF-A level in patients with severe brain edema was significantly higher (Me = 25.42 pg/ml) than in patients with moderate brain edema (Me = 29.18 pg / ml) -U Mann-Whitney test, p = 0.0258. It was also found that VEGF-D plasma level in patients with severe brain edema was significantly lower (Me = 95.25 pg / ml) than in patients with moderate brain edema (Me = 183.57 pg / ml) -Mann-Whitney test, p = 0.0034. It was also found that the plasma concentration of VEGF-D in patients with better functional status was significantly higher (Me = 185.47pg / ml) than the concentration in patients with worse functional status (Me = 111.34pg / ml) -U Mann-Whitney test, p = 0.0428. The above results proved that VEGF-A and VEGF-D present omni directional association with peritumoral brain edema in patients with intracranial tumors. VEGF-A promotes the formation of peritumoral edema, while the relationship between VEGF-D and brain edema seems to be the opposite of VEGF-A.

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VEGFD Protects Retinal Ganglion Cells and, consequently, Capillaries against Excitotoxic Injury

Cited by 15 publications

References 93 publications

Retinal Glutamate Neurotransmission: From Physiology to Pathophysiological Mechanisms of Retinal Ganglion Cell Degeneration

Retinal Glutamate Neurotransmission: From Physiology to Pathophysiological Mechanisms of Retinal Ganglion Cell Degeneration

Starvation to Glucose Reprograms Development of Neurovascular Unit in Embryonic Retinal Cells

The Different Impact of VEGF-A and VEGF-D on Peritumoral Brain Edema

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