Endorepellin Evokes Autophagy in Endothelial Cells

Poluzzi, Chiara; Casulli, Joshua; Goyal, Atul Kumar; Mercer, Thomas J.; Neill, Thomas; Iozzo, Renato V.

doi:10.1074/jbc.m114.556530

Cited by 79 publications

(123 citation statements)

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“…Endorepellin, the C-terminal domain of perlecan, induces autophagy in endothelial cells (47). Here we investigated in depth the mechanism through which endorepellin evokes autophagy and angiostasis and discovered that protracted autophagy under nutrient-rich conditions can negatively regulate angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Decorin treatment also induces autophagy via AMPK␣ phosphorylation, which increases rapidly within 30 min of treatment and is maintained for up to 2 h (66, 67). However, the slow induction of AMPK␣ by endorepellin does correlate with increases in several autophagic proteins, including Beclin 1, LC3-II, Peg3, and p62 (47).…”

Section: Discussionmentioning

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%

“…2 uble endorepellin induces autophagy in endothelial cells via the binding of its LG1/2 domains to VEGFR2 (47). This process occurs independently of the ␣2␤1 integrin and induces several autophagic markers (Beclin 1, LC3, and p62) under nutrientenriched conditions (47). In this study, we examined in detail the physical properties of endothelial cells treated with endorepellin via atomic force microscopy (AFM) imaging and nanoindentation.…”

mentioning

confidence: 99%

“…1 Both authors contributed equally to this work. 2 uble endorepellin induces autophagy in endothelial cells via the binding of its LG1/2 domains to VEGFR2 (47). This process occurs independently of the ␣2␤1 integrin and induces several autophagic markers (Beclin 1, LC3, and p62) under nutrientenriched conditions (47).…”

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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%

Section: Discussionmentioning

confidence: 99%

Section: Vegfr2 Is Required For Endorepellin-evoked Phosphorylation Omentioning

confidence: 99%

mentioning

confidence: 99%

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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Proteoglycans of basement membranes: Crucial controllers of angiogenesis, neurogenesis, and autophagy

Mongiat,

Pascal,

Poletto

et al. 2024

Proteoglycan Research

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Antiangiogenic therapy is an established method for the treatment of several cancers and vascular‐related diseases. Most of the agents employed target the vascular endothelial growth factor A, the major cytokine stimulating angiogenesis. However, the efficacy of these treatments is limited by the onset of drug resistance. Therefore, it is of fundamental importance to better understand the mechanisms that regulate angiogenesis and the microenvironmental cues that play significant role and influence patient treatment and outcome. In this context, here we review the importance of the three basement membrane (BM) heparan sulfate proteoglycans (HSPGs), namely perlecan, agrin, and collagen XVIII. These HSPGs are abundantly expressed in the vasculature and, due to their complex molecular architecture, they interact with multiple endothelial cell receptors, deeply affecting their function. Under normal conditions, these proteoglycans exert proangiogenic functions. However, in pathological conditions such as cancer and inflammation, extracellular matrix remodeling leads to the degradation of these large precursor molecules and the liberation of bioactive processed fragments displaying potent angiostatic activity. These unexpected functions have been demonstrated for the C‐terminal fragments of perlecan and collagen XVIII, endorepellin, and endostatin. These bioactive fragments can also induce autophagy in vascular endothelial cells which contributes to angiostasis. Overall, BM proteoglycans deeply affect angiogenesis counterbalancing proangiogenic signals during tumor progression and represent possible means to develop new prognostic biomarkers and novel therapeutic approaches for the treatment of solid tumors.

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