title: Endorepellin-evoked Autophagy Contributes to Angiostasis.
abstract: 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 AMP-activated kinase α, as compound C, an inhibitor of AMP-activated kinase α, 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.
authors.affiliation: From the Department of Pathology, Anatomy, and Cell Biology and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 and.
authors.forename: Atul
authors.initials: A
authors.lastname: Goyal
authors.affiliation: From the Department of Pathology, Anatomy, and Cell Biology and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 and.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Gubbiotti
authors.affiliation: the School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, Pennsylvania 19104.
authors.forename: Daphney R
authors.initials: DR
authors.lastname: Chery
authors.affiliation: the School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, Pennsylvania 19104.
authors.forename: Lin
authors.initials: L
authors.lastname: Han
authors.affiliation: From the Department of Pathology, Anatomy, and Cell Biology and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 and renato.iozzo@jefferson.edu.
authors.forename: Renato V
authors.initials: RV
authors.lastname: Iozzo
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1 / Q000378:metabolism; D055119:Elastic Modulus; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D007790:Lactosylceramides / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: C491997:BECN1 protein, human; D000071186:Beclin-1; D019812:Heparan Sulfate Proteoglycans; D007790:Lactosylceramides; D010446:Peptide Fragments; C071927:perlecan; C025575:lactotriaosylceramide; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D000263:Adenylate Kinase
keywords: AMP-activated kinase (AMPK); Beclin-1 (BECN1); angiogenesis; atomic force microscopy (AFM); perlecan; proteoglycan