title: Perivascular Mast Cells Govern Shear Stress-Induced Arteriogenesis by Orchestrating Leukocyte Function.
abstract: The body has the capacity to compensate for an occluded artery by creating a natural bypass upon increased fluid shear stress. How this mechanical force is translated into collateral artery growth (arteriogenesis) is unresolved. We show that extravasation of neutrophils mediated by the platelet receptor GPIbα and uPA results in Nox2-derived reactive oxygen radicals, which activate perivascular mast cells. These c-kit(+)/CXCR-4(+) cells stimulate arteriogenesis by recruiting additional neutrophils as well as growth-promoting monocytes and T cells. Additionally, mast cells may directly contribute to vascular remodeling and vascular cell proliferation through increased MMP activity and by supplying growth-promoting factors. Boosting mast cell recruitment and activation effectively promotes arteriogenesis, thereby protecting tissue from severe ischemic damage. We thus find that perivascular mast cells are central regulators of shear stress-induced arteriogenesis by orchestrating leukocyte function and growth factor/cytokine release, thus providing a therapeutic target for treatment of vascular occlusive diseases.
authors.affiliation: Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-Universität (LMU) Munich, 81377 Munich, Germany.
authors.forename: Omary
authors.initials: O
authors.lastname: Chillo
authors.affiliation: Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-Universität (LMU) Munich, 81377 Munich, Germany.
authors.forename: Eike Christian
authors.initials: EC
authors.lastname: Kleinert
authors.affiliation: Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-Universität (LMU) Munich, 81377 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lautz
authors.affiliation: Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-Universität (LMU) Munich, 81377 Munich, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Lasch
authors.affiliation: Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-Universität (LMU) Munich, 81377 Munich, Germany; Hospital of the University of Munich, Department of Anesthesiology, LMU Munich, 81377 Munich, Germany.
authors.forename: Judith-Irina
authors.initials: JI
authors.lastname: Pagel
authors.affiliation: Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-Universität (LMU) Munich, 81377 Munich, Germany.
authors.forename: Yvonn
authors.initials: Y
authors.lastname: Heun
authors.affiliation: Division of Arteriogenesis Research, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Troidl
authors.affiliation: Institute for Biochemistry, Medical School, Justus-Liebig-Universität, 35392 Giessen, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fischer
authors.affiliation: Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-Universität (LMU) Munich, 81377 Munich, Germany.
authors.forename: Amelia
authors.initials: A
authors.lastname: Caballero-Martinez
authors.affiliation: Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-Universität (LMU) Munich, 81377 Munich, Germany; Institute for Biochemistry, Medical School, Justus-Liebig-Universität, 35392 Giessen, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Mauer
authors.affiliation: Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-Universität (LMU) Munich, 81377 Munich, Germany.
authors.forename: Angela R M
authors.initials: ARM
authors.lastname: Kurz
authors.affiliation: Institute of Pathology, LMU Munich, 81377 Munich, Germany.
authors.forename: Gerald
authors.initials: G
authors.lastname: Assmann
authors.affiliation: Institute for Stroke and Dementia Research, LMU Munich, 81377 Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Rehberg
authors.affiliation: Institute of Basic Medical Sciences, University of Oslo, 0372 Oslo, Norway.
authors.forename: Sandip M
authors.initials: SM
authors.lastname: Kanse
authors.affiliation: Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.affiliation: Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-Universität (LMU) Munich, 81377 Munich, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Walzog
authors.affiliation: Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-Universität (LMU) Munich, 81377 Munich, Germany; Hospital of the University of Munich, Department of Otorhinolaryngology, Head and Neck Surgery, LMU Munich, 81377 Munich, Germany.
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Reichel
authors.affiliation: Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-Universität (LMU) Munich, 81377 Munich, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Mannell
authors.affiliation: Institute for Biochemistry, Medical School, Justus-Liebig-Universität, 35392 Giessen, Germany.
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Preissner
authors.affiliation: Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-Universität (LMU) Munich, 81377 Munich, Germany. Electronic address: elisabeth.deindl@med.uni-muenchen.de.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Deindl
mesh_terms: D000818:Animals; D001158:Arteries / Q000378:metabolism / Q000473:pathology; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006614:Hindlimb / Q000098:blood supply; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000166:cytology / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D000074662:NADPH Oxidase 2 / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000235:genetics*; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D013314:Stress, Mechanical; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D066253:Vascular Remodeling / Q000235:genetics*
chemical_list: C514936:CXCR4 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D019038:Platelet Glycoprotein GPIb-IX Complex; D017382:Reactive Oxygen Species; D019718:Receptors, CXCR4; C094990:adhesion receptor; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019009:Proto-Oncogene Proteins c-kit; D014568:Urokinase-Type Plasminogen Activator; D020782:Matrix Metalloproteinases