Endorepellin, the Angiostatic Module of Perlecan, Interacts with Both the α2β1 Integrin and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2)

Goyal, Atul Kumar; Pal, Nutan; Concannon, Matthew J.; Paul, Matthew R.; Doran, Michael; Poluzzi, Chiara; Sekiguchi, Kiyotoshi; Whitelock, John M.; Neill, Thomas; Iozzo, Renato V.

doi:10.1074/jbc.m111.243626

Cited by 103 publications

(143 citation statements)

References 108 publications

(114 reference statements)

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“…Indeed, we saw a non-significant reduction in vessel number in rings treated with compound C alone compared with vehicle. As endorepellin binds and signals through VEGFR2 (43,45), it is possible that compound C may interfere with the endorepellin/VEGFR2 axis.…”

Section: Discussionmentioning

confidence: 99%

“…Porcine aortic endothelial cells expressing VEGFR2 (PAER2) were described previously (43,45). The rabbit polyclonal LC3B antibody (L7543) was obtained from Sigma-Aldrich (St. Louis MO).…”

Section: Methodsmentioning

confidence: 99%

“…Endorepellin and Torin 1 Inhibit ex Vivo AngiogenesisGiven its well established angiostatic activity (34,43,47), we hypothesized that endorepellin could evoke autophagy and inhibit angiogenesis via a common pathway. To this end, we utilized an ex vivo model, the aortic ring assay (54).…”

Section: Vegfr2 Is Required For Endorepellin-evoked Phosphorylation Omentioning

confidence: 99%

“…These functional properties result from a "dual receptor antagonism" through its binding to VEGFR2 and ␣2␤1 integrin (43)…”

mentioning

confidence: 99%

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Endorepellin-evoked Autophagy Contributes to Angiostasis

Goyal

Gubbiotti

Chery

et al. 2016

Journal of Biological Chemistry

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Endorepellin, the C-terminal domain of perlecan, is an angiostatic molecule that acts as a potent inducer of autophagy via its interaction with VEGFR2. In this study, we examined the effect of endorepellin on endothelial cells using atomic force microscopy. Soluble endorepellin caused morphological and biophysical changes such as an increase in cell surface roughness and cell height. Surprisingly, these changes were not accompanied by alterations in the endothelial cell elastic modulus. We discovered that endorepellin-induced autophagic flux led to co-localization of mammalian target of rapamycin with LC3-positive autophagosomes. Endorepellin functioned upstream of AMPactivated kinase ␣, as compound C, an inhibitor of AMP-activated kinase ␣, abrogated endorepellin-mediated activation and co-localization of Beclin 1 and LC3, thereby reducing autophagic progression. Functionally, we discovered that both endorepellin and Torin 1, a canonical autophagic inducer, blunted ex vivo angiogenesis. We conclude that autophagy is a novel mechanism by which endorepellin promotes angiostasis independent of nutrient deprivation.

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Section: Discussionmentioning

confidence: 99%

“…Porcine aortic endothelial cells expressing VEGFR2 (PAER2) were described previously (43,45). The rabbit polyclonal LC3B antibody (L7543) was obtained from Sigma-Aldrich (St. Louis MO).…”

Section: Methodsmentioning

confidence: 99%

Section: Vegfr2 Is Required For Endorepellin-evoked Phosphorylation Omentioning

confidence: 99%

“…These functional properties result from a "dual receptor antagonism" through its binding to VEGFR2 and ␣2␤1 integrin (43)…”

mentioning

confidence: 99%

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Endorepellin-evoked Autophagy Contributes to Angiostasis

Goyal

Gubbiotti

Chery

et al. 2016

Journal of Biological Chemistry

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“…To corroborate the role of decorin in modulating the VEGFA/ VEGFR2 axis, we used PAE-VEGFR2 cells stably expressing the luciferase gene under the control of the human VEGFA promoter (38,39). We found that decorin induced a significant inhibition of VEGFA promoter luciferase activity within 6 h of treatment (P < 0.001) (Fig.…”

Section: Decorin Requires Vegfr2 For Its Downstream Signaling Andmentioning

confidence: 99%

Decorin causes autophagy in endothelial cells via Peg3

Buraschi

Neill

Goyal

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance We identified a function for a member of the extracellular matrix in the regulation of autophagy. Decorin, a member of the small leucine-rich proteoglycan family and an established pan-receptor tyrosine kinase inhibitor, evokes endothelial cell autophagy and inhibits angiogenesis. This process is mediated by a high-affinity interaction with VEGFR2 which leads to increased levels of Peg3, a tumor-suppressor gene. We provide mechanistic evidence that Peg3 is required to maintain basal levels of Beclin 1, a major autophagic marker. These data provide a paradigmatic shift for other soluble matrix constituents to regulate autophagy.

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Glycosaminoglycan and Proteoglycan Biotherapeutics in Articular Cartilage Protection and Repair Strategies: Novel Approaches to Visco‐supplementation in Orthobiologics

Hayes

Melrose

2019

Advanced Therapeutics

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The aim of this study is to review developments in glycosaminoglycan and proteoglycan research relevant to cartilage repair biology and in particular the treatment of osteoarthritis (OA). Glycosaminoglycans decorate a diverse range of extracellular matrix and cell associated proteoglycans conveying structural organization and physico-chemical properties to tissues. They play key roles mediating cellular interactions with bioactive growth factors, cytokines, and morphogenetic proteins, and structural fibrillar collagens, cell interactive and extracellular matrix proteoglycans, and glycoproteins which define tissue function. Proteoglycan degradation detrimentally affects tissue functional properties. Therapeutic strategies have been developed to counter these degenerative changes. Neo-proteoglycans prepared from chondroitin sulfate or hyaluronan and hyaluronan or collagen-binding peptides emulate the interactive, water imbibing, weight bearing, and surface lubricative properties of native proteoglycans. Many neo-proteoglycans outperform native proteoglycans in terms of water imbibition, matrix stabilization, and resistance to proteolytic degradation. The biospecificity of recombinant proteoglycans however, provides precise attachment to native target molecules. Visco-supplements augmented with growth factors/therapeutic cells, hyaluronan, and lubricin (orthobiologicals) have the capacity to lubricate and protect cartilage, control inflammation, and promote cartilage repair and regeneration of early cartilage lesions and may represent a more effective therapeutic approach to the treatment of mild to moderate OA and deserve further study.Similar protective perineural net structures assembled from the lectican proteoglycan family and HA also occur in the CNS/PNS. These so called perineuronal nets are visualized by immunolocalization of MAb 1B5 (+) epitope in rat brain (e) and pericellular 1B5(+) epitope expression by isolated neurons (f). Scale bars 100 µm.

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Endorepellin, the Angiostatic Module of Perlecan, Interacts with Both the α2β1 Integrin and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2)

Cited by 103 publications

References 108 publications

Endorepellin-evoked Autophagy Contributes to Angiostasis

Endorepellin-evoked Autophagy Contributes to Angiostasis

Decorin causes autophagy in endothelial cells via Peg3

Glycosaminoglycan and Proteoglycan Biotherapeutics in Articular Cartilage Protection and Repair Strategies: Novel Approaches to Visco‐supplementation in Orthobiologics

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