Novel anti-angiogenic PEDF-derived small peptides mitigate choroidal neovascularization

Wang, Shoujian; Darjatmoko, Soesiawati R.; Fisk, Debra L.; Shahi, Pawan K; Pattnaik, Bikash R.; Sorenson, Christine M.; Bhowmick, Reshma; Volpert, Olga V.; Albert, Daniel M.; Melgar-Asensio, Ignacio; Henkin, Jack

doi:10.1016/j.exer.2019.107798

Cited by 26 publications

(16 citation statements)

References 48 publications

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“…PEDF has anti-angiogenic, anti-tumorigenic, anti-inflammatory, anti-oxidative, neurotrophic, neuroprotective, and anti-vasopermeability properties [ 57 , 58 , 59 , 60 , 61 ]. In the present study, NU335, a novel bioactive PEDF-derived peptide [ 28 ], ameliorated SE-induced vasogenic edema in the PC. Similar to EGCG, NU335 inhibited the p38 MAPK–PI3K/AKT–eNOS signaling pathway in endothelial cells under physiological and post-SE conditions.…”

Section: Discussionmentioning

confidence: 77%

“…On the other hand, various insults such as stroke and head trauma also evoke vasogenic edema that increases intracranial pressure, leading to fatal conditions [ 91 ]. Furthermore, retinal vascular permeability is increased in diabetic retinopathy and exudative macular degeneration that cause blindness [ 28 , 92 , 93 ]. Currently, corticosteroids and agents blocking VEGF are the predominant treatment options for brain edema and retina macular edema, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, polyphenol (–)-epigallocatechin-3- O -gallate (EGCG) binds to 67LR and induces apoptosis in cancer cells [ 24 , 25 , 26 ]. Similar to EGCG, the full-length pigment epithelium-derived factor (PEDF) and its derived peptides bind to 67LR and inhibit neovascularization [ 27 , 28 ]. Interestingly, EGCG protects endothelial cells from apoptosis [ 29 , 30 ], and it reduces vascular permeability in vitro [ 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

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Epigallocatechin-3-Gallate and PEDF 335 Peptide, 67LR Activators, Attenuate Vasogenic Edema, and Astroglial Degeneration Following Status Epilepticus

et al. 2020

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Non-integrin 67-kDa laminin receptor (67LR) is involved in cell adherence to the basement membrane, and it regulates the interactions between laminin and other receptors. The dysfunction of 67LR leads to serum extravasation via blood-brain barrier (BBB) disruption. Polyphenol (–)-epigallocatechin-3-O-gallate (EGCG) and pigment epithelium-derived factor (PEDF) bind to 67LR and inhibit neovascularization. Therefore, in the present study, we investigated the effects of EGCG and NU335, a PEDF-derive peptide, on BBB integrity and their possible underlying mechanisms against vasogenic edema formation induced by status epilepticus (SE, a prolonged seizure activity). Following SE, both EGCG and NU335 attenuated serum extravasation and astroglial degeneration in the rat piriform cortex (PC). Both EGCG and NU335 reversely regulated phosphatidylinositol 3 kinase (PI3K)/AKT–eNOS (endothelial nitric oxide synthase) mediated BBB permeability and aquaporin 4 (AQP4) expression in endothelial cells and astrocytes through the p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways, respectively. Furthermore, EGCG and NU335 decreased p47Phox (a nicotinamide adenine dinucleotide phosphate oxidase subunit) expression in astrocytes under physiological and post-SE conditions. Therefore, we suggest that EGCG and PEDF derivatives may activate 67LR and its downstream effectors, and they may be considerable anti-vasogenic edema agents.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Epigallocatechin-3-Gallate and PEDF 335 Peptide, 67LR Activators, Attenuate Vasogenic Edema, and Astroglial Degeneration Following Status Epilepticus

et al. 2020

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“…VEGF is frequently targeted to prevent neovascularization, with neutralizing antibodies or VEGF receptor antagonists being tested at the clinical level [44]. Another therapeutic target is the anti-angiogenic cytokine PEDF where the increased expression of PEDF or use of PEDF-derived small peptides has significant protective effects in retinal neovascularization diseases [49][50][51]. The importance of understanding neovascularization mechanisms in AMD was one of the rationales for this study.…”

Section: Discussionmentioning

confidence: 99%

Effects of FTMT Expression by Retinal Pigment Epithelial Cells on Features of Angiogenesis

Buyandelger

Walker

Yanagisawa

et al. 2020

IJMS

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Aberrant angiogenesis is a pathological feature of a number of diseases and arises from the uncoordinated expression of angiogenic factors as response to different cellular stresses. Age-related macular degeneration (AMD), a leading cause of vision loss, can result from pathological angiogenesis. As a mutation in the mitochondrial ferritin (FTMT) gene has been associated with AMD, its possible role in modulating angiogenic factors and angiogenesis was investigated. FTMT is an iron-sequestering protein primarily expressed in metabolically active cells and tissues with high oxygen demand, including retina. In this study, we utilized the human retinal pigment epithelial cell line ARPE-19, both as undifferentiated and differentiated cells. The effects of proinflammatory cytokines, FTMT knockdown, and transient and stable overexpression of FTMT were investigated on expression of pro-angiogenic vascular endothelial growth factor (VEGF) and anti-angiogenic pigment epithelial-derived factor (PEDF). Proinflammatory cytokines induced FTMT and VEGF expression, while NF-κB inhibition significantly reduced FTMT expression. VEGF protein and mRNA expression were significantly increased in FTMT-silenced ARPE-19 cells. Using an in vitro angiogenesis assay with endothelial cells, we showed that conditioned media from FTMT-overexpressing cells had significant antiangiogenic effects. Collectively, our findings indicate that increased levels of FTMT inhibit angiogenesis, possibly by reducing levels of VEGF and increasing PEDF expression. The cellular models developed can be used to investigate if increased FTMT may be protective in angiogenic diseases, such as AMD.

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“…To test if the antiangiogenic treatment might modify healing outcomes in the rabbit model, wounds were injected with either rPEDF or PEDF peptide PEDF-335, a peptide previously shown to be highly antiangiogenic. 25 Wounds were injected once every 3 days from day 4 to day 19. Similar to prior studies in mouse wounds, the partial inhibition of wound angiogenesis had no effect on wound closure ( We then evaluated if rPEDF or PEDF-355 treatment could affect collagen I and III mRNA expression in the scars.…”

Section: Pedf Treatment Inhibits Angiogenesis and Reduces Collagen mentioning

confidence: 99%

Pigment epithelium‐derived factor attenuates angiogenesis and collagen deposition in hypertrophic scars

Chen

Shi

et al. 2020

Wound Repair Regeneration

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Scar forming wounds are often characterized by higher levels of vascularity than non‐scarring wounds and normal skin, and inhibition of angiogenesis has been shown to inhibit scar formation in some model systems. The rabbit ear hypertrophic scar (HS) model has been widely used to study the mechanisms that underlie the development of HS as well as the effectiveness of various treatments. Although the rabbit ear HS model is well characterized in terms of scar formation, the rate and level of angiogenesis has not been investigated in this model, and the cause‐effect relationship between angiogenesis and rabbit HSs has not been examined. In the current study, full‐thickness excisional wounds were created on the ventral side of New Zealand White rabbit ears to induce HS formation, and the dynamic pattern of angiogenesis and the expression of angiogenic regulatory factors were examined over time. Blood vessel density was found to peak at 2.7% on day 14 post‐wounding, decreasing to 1.7% by day 28. mRNA levels of the proangiogenic factor VEGF‐A peaked at day 14, while the expression of the antiangiogenic factors pigment epithelium‐derived factor (PEDF) and thrombospondin 1 (TSP1) peaked at day 28 post‐wounding. To examine whether inhibition of angiogenesis influences HS formation in this model, wounds were treated with exogenous soluble antiangiogenic agents including recombinant PEDF (rPEDF) and a functional PEDF peptide (PEDF‐335). rPEDF and PEDF‐335 were administered intradermally from day 4 post‐wounding every 3 days until day 19. Intradermal injection of rPEDF or PEDF‐335 both led to decreased angiogenesis and decreased collagen deposition at the wound site. The results support the utility of antiangiogenic therapies, including rPEDF/PEDF‐335, as a potential new strategy for the prevention or treatment of HSs.

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Novel anti-angiogenic PEDF-derived small peptides mitigate choroidal neovascularization

Cited by 26 publications

References 48 publications

Epigallocatechin-3-Gallate and PEDF 335 Peptide, 67LR Activators, Attenuate Vasogenic Edema, and Astroglial Degeneration Following Status Epilepticus

Epigallocatechin-3-Gallate and PEDF 335 Peptide, 67LR Activators, Attenuate Vasogenic Edema, and Astroglial Degeneration Following Status Epilepticus

Effects of FTMT Expression by Retinal Pigment Epithelial Cells on Features of Angiogenesis

Pigment epithelium‐derived factor attenuates angiogenesis and collagen deposition in hypertrophic scars

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