title: A differential role for CD248 (Endosialin) in PDGF-mediated skeletal muscle angiogenesis.
abstract: CD248 (Endosialin) is a type 1 membrane protein involved in developmental and pathological angiogenesis through its expression on pericytes and regulation of PDGFRβ signalling. Here we explore the function of CD248 in skeletal muscle angiogenesis. Two distinct forms of capillary growth (splitting and sprouting) can be induced separately by increasing microcirculatory shear stress (chronic vasodilator treatment) or by inducing functional overload (extirpation of a synergistic muscle). We show that CD248 is present on pericytes in muscle and that CD248-/- mice have a specific defect in capillary sprouting. In contrast, splitting angiogenesis is independent of CD248 expression. Endothelial cells respond to pro-sprouting angiogenic stimulus by up-regulating gene expression for HIF1α, angiopoietin 2 and its receptor TEK, PDGF-B and its receptor PDGFRβ; this response did not occur following a pro-splitting angiogenic stimulus. In wildtype mice, defective sprouting angiogenesis could be mimicked by blocking PDGFRβ signalling using the tyrosine kinase inhibitor Imatinib mesylate. We conclude that CD248 is required for PDGFRβ-dependant capillary sprouting but not splitting angiogenesis, and identify a new role for CD248 expressed on pericytes in the early stages of physiological angiogenesis during muscle remodelling.
authors.affiliation: Rheumatology Research Group, Centre for Translational Inflammation Research, University of Birmingham, Birmingham, West Midlands, United Kingdom.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Naylor
authors.affiliation: Rheumatology Research Group, Centre for Translational Inflammation Research, University of Birmingham, Birmingham, West Midlands, United Kingdom; Systems Science for Health, University of Birmingham, Birmingham, West Midlands, United Kingdom.
authors.forename: Helen M
authors.initials: HM
authors.lastname: McGettrick
authors.affiliation: Rheumatology Research Group, Centre for Translational Inflammation Research, University of Birmingham, Birmingham, West Midlands, United Kingdom.
authors.forename: William D
authors.initials: WD
authors.lastname: Maynard
authors.affiliation: Rheumatology Research Group, Centre for Translational Inflammation Research, University of Birmingham, Birmingham, West Midlands, United Kingdom.
authors.forename: Philippa
authors.initials: P
authors.lastname: May
authors.affiliation: Rheumatology Research Group, Centre for Translational Inflammation Research, University of Birmingham, Birmingham, West Midlands, United Kingdom.
authors.forename: Francesca
authors.initials: F
authors.lastname: Barone
authors.affiliation: Rheumatology Research Group, Centre for Translational Inflammation Research, University of Birmingham, Birmingham, West Midlands, United Kingdom.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Croft
authors.affiliation: Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire, United Kingdom.
authors.forename: Stuart
authors.initials: S
authors.lastname: Egginton
authors.affiliation: Rheumatology Research Group, Centre for Translational Inflammation Research, University of Birmingham, Birmingham, West Midlands, United Kingdom; Systems Science for Health, University of Birmingham, Birmingham, West Midlands, United Kingdom.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Buckley
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D000068877:Imatinib Mesylate; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics*; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D011224:Prazosin / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D042702:Angiopoietin-2; D015703:Antigens, CD; D001549:Benzamides; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C509258:tumor endothelial marker 1, mouse; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor; D011224:Prazosin