title: Extracellular ubiquitin increases expression of angiogenic molecules and stimulates angiogenesis in cardiac microvascular endothelial cells.
abstract: Extracellular Ub is an immune modulator that plays a role in suppression of inflammation, organ injury, myocyte apoptosis, and fibrosis. The purpose of this study was to investigate the effects of extracellular Ub on the process of cardiac angiogenesis. CMECs and aortic tissue were isolated from rats to measure changes in angiogenic protein levels and to assess angiogenic responses to extracellular Ub. In CMECs, extracellular Ub increased protein levels of VEGF-A and MMP-2, known angiogenesis regulators. CMECs demonstrated enhanced rearrangement of fibrillar actin and migration in response to Ub treatment. Ub-treated CMECs demonstrated an increase in tube network formation which was inhibited by the CXCR4 receptor antagonist, AMD3100. Methylated Ub, unable to form polyubiquitin chains, enhanced tube network formation. Aortic ring sprouting assays demonstrated that Ub increases microvessel sprouting in the Matrigel. The results of our study suggest a novel role for extracellular Ub in cardiac angiogenesis, providing evidence that extracellular Ub, at least in part acting via the CXCR4 receptor, has the potential to facilitate the process of angiogenesis in myocardial endothelial cells.
authors.affiliation: Department of Biomedical Sciences, James H Quillen College of Medicine, James H Quillen Veterans Affairs Medical Center, East Tennessee State University, Johnson City, Tennessee, USA.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Steagall
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Daniels
authors.forename: Suman
authors.initials: S
authors.lastname: Dalal
authors.forename: William L
authors.initials: WL
authors.lastname: Joyner
authors.forename: Mahipal
authors.initials: M
authors.lastname: Singh
authors.forename: Krishna
authors.initials: K
authors.lastname: Singh
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D055806:Microvessels / Q000166:cytology / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D025801:Ubiquitin / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D025801:Ubiquitin; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat
keywords: VEGF-A; angiogenesis; cardiac microvascular endothelial cells; heart; ubiquitin