NGF Prevents Loss of TrkA/VEGFR2 Cells, and VEGF Isoform Dysregulation in the Retina of Adult Diabetic Rats

Fico, Elena; Rosso, Pamela; Triaca, Viviana; Segatto, Marco; Lambìase, Alessandro; Tirassa, Paola

doi:10.3390/cells11203246

Cited by 6 publications

(5 citation statements)

References 44 publications

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“…In contrast to Scg3, VEGF drives DR-associated vascular pathology primarily through increased levels of ligand with estimates of a >100-fold increase in VEGF-A in the vitreous of PDR patients [ 40 , 41 ]. The low specificity and absence of apparent DR-related differential binding of VEGF observed in our study is consistent with other reports that VEGF receptors (VEGFRs) are minimally elevated or even decreased in diabetic rodents and patients [ 41 , 42 ]. The binding pattern is also consistent with the ubiquitous presence of VEGFRs in retinal vessels in control and DR mice, as discussed previously [ 15 ].…”

Section: Discussionsupporting

confidence: 93%

Secretogranin III Selectively Promotes Vascular Leakage in the Deep Vascular Plexus of Diabetic Retinopathy

Waduge

et al. 2023

IJMS

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Diabetic retinopathy (DR), a leading cause of vision loss in working-age adults, induces mosaic patterns of vasculopathy that may be associated with spatial heterogeneity of intraretinal endothelial cells. We recently reported that secretogranin III (Scg3), a neuron-derived angiogenic and vascular leakage factor, selectively binds retinal vessels of diabetic but not healthy mice. Here, we investigated endothelial heterogeneity of three retinal vascular plexuses in DR pathogenesis and the therapeutic implications. Our unique in vivo ligand binding assay detected a 22.7-fold increase in Scg3 binding to retinal vessels of diabetic mice relative to healthy mice. Functional immunohistochemistry revealed that Scg3 predominantly binds to the DR-stressed CD31− deep retinal vascular plexus but not to the relatively healthy CD31+ superficial and intermediate plexuses within the same diabetic retina. In contrast, VEGF bound to healthy and diabetic retinal vessels indiscriminately with low activity. FITC-dextran assays indicated that selectively increased retinal vascular leakage coincides with Scg3 binding in diabetic mice that was independent of VEGF, whereas VEGF-induced leakage did not distinguish between diabetic and healthy mice. Dose–response curves showed that the anti-Scg3 humanized antibody (hAb) and anti-VEGF aflibercept alleviated DR leakage with equivalent efficacies, and that the combination acted synergistically. These findings suggest: (i) the deep plexus is highly sensitive to DR; (ii) Scg3 binding to the DR deep plexus coincides with the loss of CD31 and compromised endothelial junctions; (iii) anti-Scg3 hAb alleviates vascular leakage by selectively targeting the DR-stressed deep plexus within the same diabetic retina; (iv) combined anti-Scg3 and anti-VEGF treatments synergistically ameliorate DR through distinct mechanisms.

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Section: Discussionsupporting

confidence: 93%

Secretogranin III Selectively Promotes Vascular Leakage in the Deep Vascular Plexus of Diabetic Retinopathy

Waduge

et al. 2023

IJMS

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“…More clinical data support the relationship between repeated anti-VEGF injections and the development of ocular hypertension or glaucoma [ 61 , 62 ]. Moreover, very recent preclinical data suggest that the effects of VEGF in DR can be modulated by the concomitant presence of NGF [ 63 ]. Therefore, regulating factors upstream of VEGF have received attention as a desirable therapeutic approach to eliminating off-target effects.…”

Section: Management Of Neovascular Retinal Diseasesmentioning

confidence: 99%

Pharmacotherapy and Nutritional Supplements for Neovascular Eye Diseases

Rusciano

Bagnoli

2023

Medicina

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In this review, we aim to provide an overview of the recent findings about the treatment of neovascular retinal diseases. The use of conventional drugs and nutraceuticals endowed with antioxidant and anti-inflammatory properties that may support conventional therapies will be considered, with the final aim of achieving risk reduction (prevention) and outcome improvement (cooperation between treatments) of such sight-threatening proliferative retinopathies. For this purpose, we consider a medicinal product one that contains well-defined compound(s) with proven pharmacological and therapeutic effects, usually given for the treatment of full-blown diseases. Rarely are prescription drugs given for preventive purposes. A dietary supplement refers to a compound (often an extract or a mixture) used in the prevention or co-adjuvant treatment of a given pathology. However, it must be kept in mind that drug–supplement interactions may exist and might affect the efficacy of certain drug treatments. Moreover, the distinction between medicinal products and dietary supplements is not always straightforward. For instance, melatonin is formulated as a medicinal product for the treatment of sleep and behavioral problems; at low doses (usually below 1 mg), it is considered a nutraceutical, while at higher doses, it is sold as a psychotropic drug. Despite their lower status with respect to drugs, increasing evidence supports the notion of the beneficial effects of dietary supplements on proliferative retinopathies, a major cause of vision loss in the elderly. Therefore, we believe that, on a patient-by-patient basis, the administration of nutraceuticals, either alone or in association, could benefit many patients, delaying the progression of their disease and likely improving the efficacy of pharmaceutical drugs.

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“…Thus, cannabinoid drugs may have both neuroprotective and vasoprotective effects in DR. VEGFA is known to exert a neuroprotective effect via the VEGF receptor 2. The topical administration of nerve growth factor (NGF) reduces inflammatory and pro-apoptotic intracellular signals and maintains VEGF receptor 2 expression in the RGCs of diabetic rats [ 115 ]. In the retinas of diabetic rats, the expression of VEGF receptor 2 is decreased.…”

Section: Therapeutic Approaches For Retinal Cell Death In Drmentioning

confidence: 99%

“…In the retinas of diabetic rats, the expression of VEGF receptor 2 is decreased. Thus, NGF may contribute to the switch from proangiogenic and apoptotic phases to the neuroprotective phase of VEGF in early DR [ 115 ]. Another study indicated that the topical administration of NGF successfully prevented RGC loss, pericyte loss, and acellular capillary development in animal diabetic models [ 116 ].…”

Section: Therapeutic Approaches For Retinal Cell Death In Drmentioning

confidence: 99%

Neurovascular Cell Death and Therapeutic Strategies for Diabetic Retinopathy

Oshitari

2023

IJMS

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Diabetic retinopathy (DR) is a major complication of diabetes and a leading cause of blindness worldwide. DR was recently defined as a neurovascular disease associated with tissue-specific neurovascular impairment of the retina in patients with diabetes. Neurovascular cell death is the main cause of neurovascular impairment in DR. Thus, neurovascular cell protection is a potential therapy for preventing the progression of DR. Growing evidence indicates that a variety of cell death pathways, such as apoptosis, necroptosis, ferroptosis, and pyroptosis, are associated with neurovascular cell death in DR. These forms of regulated cell death may serve as therapeutic targets for ameliorating the pathogenesis of DR. This review focuses on these cell death mechanisms and describes potential therapies for the treatment of DR that protect against neurovascular cell death.

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NGF Prevents Loss of TrkA/VEGFR2 Cells, and VEGF Isoform Dysregulation in the Retina of Adult Diabetic Rats

Cited by 6 publications

References 44 publications

Secretogranin III Selectively Promotes Vascular Leakage in the Deep Vascular Plexus of Diabetic Retinopathy

Secretogranin III Selectively Promotes Vascular Leakage in the Deep Vascular Plexus of Diabetic Retinopathy

Pharmacotherapy and Nutritional Supplements for Neovascular Eye Diseases

Neurovascular Cell Death and Therapeutic Strategies for Diabetic Retinopathy

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