title: Endothelial Dysfunction, and A Prothrombotic, Proinflammatory Phenotype Is Caused by Loss of Mitochondrial Thioredoxin Reductase in Endothelium.
abstract: Although the investigation on the importance of mitochondria-derived reactive oxygen species (ROS) in endothelial function has been gaining momentum, little is known on the precise role of the individual components involved in the maintenance of a delicate ROS balance. Here we studied the impact of an ongoing dysregulated redox homeostasis by examining the effects of endothelial cell-specific deletion of murine thioredoxin reductase 2 (Txnrd2), a key enzyme of mitochondrial redox control.
  
  
  
  We analyzed the impact of an inducible, endothelial cell-specific deletion of Txnrd2 on vascular remodeling in the adult mouse after femoral artery ligation. Laser Doppler analysis and histology revealed impaired angiogenesis and arteriogenesis. In addition, endothelial loss of Txnrd2 resulted in a prothrombotic, proinflammatory vascular phenotype, manifested as intravascular cellular deposits, as well as microthrombi. This phenotype was confirmed by an increased leukocyte response toward interleukin-1 in the mouse cremaster model. In vitro, we could confirm the attenuated angiogenesis measured in vivo, which was accompanied by increased ROS and an impaired mitochondrial membrane potential. Ex vivo analysis of femoral arteries revealed reduced flow-dependent vasodilation in endothelial cell Txnrd2-deficient mice. This endothelial dysfunction could be, at least partly, ascribed to inadequate nitric oxide signaling.
  
  
  
  We conclude that the maintenance of mitochondrial ROS via Txnrd2 in endothelial cells is necessary for an intact vascular homeostasis and remodeling and that Txnrd2 plays a vitally important role in balancing mitochondrial ROS production in the endothelium.
authors.affiliation: From the Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany (J.K., H.S., J.-I.P., M.R., M.S., J.H., O.C., K.M.S., J.Q., K.P., P.K., B.U., J.P., E.D., U.P., H.B.); Stress and Immunity Lab, Department of Anesthesiology, Ludwig-Maximilians-University Hospital of Munich, Munich, Germany (J.-I.P.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (U.P.); Partner site Munich Heart Alliance, Munich, Germany (U.P.); Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany (S.M., T.K.); and Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Munich, Germany (M.C.).
authors.forename: Julian
authors.initials: J
authors.lastname: Kirsch
authors.affiliation: From the Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany (J.K., H.S., J.-I.P., M.R., M.S., J.H., O.C., K.M.S., J.Q., K.P., P.K., B.U., J.P., E.D., U.P., H.B.); Stress and Immunity Lab, Department of Anesthesiology, Ludwig-Maximilians-University Hospital of Munich, Munich, Germany (J.-I.P.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (U.P.); Partner site Munich Heart Alliance, Munich, Germany (U.P.); Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany (S.M., T.K.); and Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Munich, Germany (M.C.).
authors.forename: Holger
authors.initials: H
authors.lastname: Schneider
authors.affiliation: From the Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany (J.K., H.S., J.-I.P., M.R., M.S., J.H., O.C., K.M.S., J.Q., K.P., P.K., B.U., J.P., E.D., U.P., H.B.); Stress and Immunity Lab, Department of Anesthesiology, Ludwig-Maximilians-University Hospital of Munich, Munich, Germany (J.-I.P.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (U.P.); Partner site Munich Heart Alliance, Munich, Germany (U.P.); Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany (S.M., T.K.); and Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Munich, Germany (M.C.).
authors.forename: Judith-Irina
authors.initials: JI
authors.lastname: Pagel
authors.affiliation: From the Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany (J.K., H.S., J.-I.P., M.R., M.S., J.H., O.C., K.M.S., J.Q., K.P., P.K., B.U., J.P., E.D., U.P., H.B.); Stress and Immunity Lab, Department of Anesthesiology, Ludwig-Maximilians-University Hospital of Munich, Munich, Germany (J.-I.P.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (U.P.); Partner site Munich Heart Alliance, Munich, Germany (U.P.); Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany (S.M., T.K.); and Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Munich, Germany (M.C.).
authors.forename: Markus
authors.initials: M
authors.lastname: Rehberg
authors.affiliation: From the Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany (J.K., H.S., J.-I.P., M.R., M.S., J.H., O.C., K.M.S., J.Q., K.P., P.K., B.U., J.P., E.D., U.P., H.B.); Stress and Immunity Lab, Department of Anesthesiology, Ludwig-Maximilians-University Hospital of Munich, Munich, Germany (J.-I.P.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (U.P.); Partner site Munich Heart Alliance, Munich, Germany (U.P.); Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany (S.M., T.K.); and Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Munich, Germany (M.C.).
authors.forename: Miriam
authors.initials: M
authors.lastname: Singer
authors.affiliation: From the Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany (J.K., H.S., J.-I.P., M.R., M.S., J.H., O.C., K.M.S., J.Q., K.P., P.K., B.U., J.P., E.D., U.P., H.B.); Stress and Immunity Lab, Department of Anesthesiology, Ludwig-Maximilians-University Hospital of Munich, Munich, Germany (J.-I.P.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (U.P.); Partner site Munich Heart Alliance, Munich, Germany (U.P.); Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany (S.M., T.K.); and Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Munich, Germany (M.C.).
authors.forename: Juliane
authors.initials: J
authors.lastname: Hellfritsch
authors.affiliation: From the Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany (J.K., H.S., J.-I.P., M.R., M.S., J.H., O.C., K.M.S., J.Q., K.P., P.K., B.U., J.P., E.D., U.P., H.B.); Stress and Immunity Lab, Department of Anesthesiology, Ludwig-Maximilians-University Hospital of Munich, Munich, Germany (J.-I.P.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (U.P.); Partner site Munich Heart Alliance, Munich, Germany (U.P.); Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany (S.M., T.K.); and Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Munich, Germany (M.C.).
authors.forename: Omary
authors.initials: O
authors.lastname: Chillo
authors.affiliation: From the Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany (J.K., H.S., J.-I.P., M.R., M.S., J.H., O.C., K.M.S., J.Q., K.P., P.K., B.U., J.P., E.D., U.P., H.B.); Stress and Immunity Lab, Department of Anesthesiology, Ludwig-Maximilians-University Hospital of Munich, Munich, Germany (J.-I.P.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (U.P.); Partner site Munich Heart Alliance, Munich, Germany (U.P.); Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany (S.M., T.K.); and Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Munich, Germany (M.C.).
authors.forename: Kai Michael
authors.initials: KM
authors.lastname: Schubert
authors.affiliation: From the Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany (J.K., H.S., J.-I.P., M.R., M.S., J.H., O.C., K.M.S., J.Q., K.P., P.K., B.U., J.P., E.D., U.P., H.B.); Stress and Immunity Lab, Department of Anesthesiology, Ludwig-Maximilians-University Hospital of Munich, Munich, Germany (J.-I.P.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (U.P.); Partner site Munich Heart Alliance, Munich, Germany (U.P.); Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany (S.M., T.K.); and Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Munich, Germany (M.C.).
authors.forename: Jiehua
authors.initials: J
authors.lastname: Qiu
authors.affiliation: From the Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany (J.K., H.S., J.-I.P., M.R., M.S., J.H., O.C., K.M.S., J.Q., K.P., P.K., B.U., J.P., E.D., U.P., H.B.); Stress and Immunity Lab, Department of Anesthesiology, Ludwig-Maximilians-University Hospital of Munich, Munich, Germany (J.-I.P.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (U.P.); Partner site Munich Heart Alliance, Munich, Germany (U.P.); Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany (S.M., T.K.); and Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Munich, Germany (M.C.).
authors.forename: Kristin
authors.initials: K
authors.lastname: Pogoda
authors.affiliation: From the Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany (J.K., H.S., J.-I.P., M.R., M.S., J.H., O.C., K.M.S., J.Q., K.P., P.K., B.U., J.P., E.D., U.P., H.B.); Stress and Immunity Lab, Department of Anesthesiology, Ludwig-Maximilians-University Hospital of Munich, Munich, Germany (J.-I.P.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (U.P.); Partner site Munich Heart Alliance, Munich, Germany (U.P.); Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany (S.M., T.K.); and Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Munich, Germany (M.C.).
authors.forename: Petra
authors.initials: P
authors.lastname: Kameritsch
authors.affiliation: From the Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany (J.K., H.S., J.-I.P., M.R., M.S., J.H., O.C., K.M.S., J.Q., K.P., P.K., B.U., J.P., E.D., U.P., H.B.); Stress and Immunity Lab, Department of Anesthesiology, Ludwig-Maximilians-University Hospital of Munich, Munich, Germany (J.-I.P.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (U.P.); Partner site Munich Heart Alliance, Munich, Germany (U.P.); Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany (S.M., T.K.); and Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Munich, Germany (M.C.).
authors.forename: Bernd
authors.initials: B
authors.lastname: Uhl
authors.affiliation: From the Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany (J.K., H.S., J.-I.P., M.R., M.S., J.H., O.C., K.M.S., J.Q., K.P., P.K., B.U., J.P., E.D., U.P., H.B.); Stress and Immunity Lab, Department of Anesthesiology, Ludwig-Maximilians-University Hospital of Munich, Munich, Germany (J.-I.P.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (U.P.); Partner site Munich Heart Alliance, Munich, Germany (U.P.); Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany (S.M., T.K.); and Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Munich, Germany (M.C.).
authors.forename: Joachim
authors.initials: J
authors.lastname: Pircher
authors.affiliation: From the Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany (J.K., H.S., J.-I.P., M.R., M.S., J.H., O.C., K.M.S., J.Q., K.P., P.K., B.U., J.P., E.D., U.P., H.B.); Stress and Immunity Lab, Department of Anesthesiology, Ludwig-Maximilians-University Hospital of Munich, Munich, Germany (J.-I.P.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (U.P.); Partner site Munich Heart Alliance, Munich, Germany (U.P.); Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany (S.M., T.K.); and Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Munich, Germany (M.C.).
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Deindl
authors.affiliation: From the Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany (J.K., H.S., J.-I.P., M.R., M.S., J.H., O.C., K.M.S., J.Q., K.P., P.K., B.U., J.P., E.D., U.P., H.B.); Stress and Immunity Lab, Department of Anesthesiology, Ludwig-Maximilians-University Hospital of Munich, Munich, Germany (J.-I.P.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (U.P.); Partner site Munich Heart Alliance, Munich, Germany (U.P.); Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany (S.M., T.K.); and Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Munich, Germany (M.C.).
authors.forename: Susanna
authors.initials: S
authors.lastname: Müller
authors.affiliation: From the Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany (J.K., H.S., J.-I.P., M.R., M.S., J.H., O.C., K.M.S., J.Q., K.P., P.K., B.U., J.P., E.D., U.P., H.B.); Stress and Immunity Lab, Department of Anesthesiology, Ludwig-Maximilians-University Hospital of Munich, Munich, Germany (J.-I.P.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (U.P.); Partner site Munich Heart Alliance, Munich, Germany (U.P.); Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany (S.M., T.K.); and Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Munich, Germany (M.C.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Kirchner
authors.affiliation: From the Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany (J.K., H.S., J.-I.P., M.R., M.S., J.H., O.C., K.M.S., J.Q., K.P., P.K., B.U., J.P., E.D., U.P., H.B.); Stress and Immunity Lab, Department of Anesthesiology, Ludwig-Maximilians-University Hospital of Munich, Munich, Germany (J.-I.P.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (U.P.); Partner site Munich Heart Alliance, Munich, Germany (U.P.); Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany (S.M., T.K.); and Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Munich, Germany (M.C.).
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pohl
authors.affiliation: From the Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany (J.K., H.S., J.-I.P., M.R., M.S., J.H., O.C., K.M.S., J.Q., K.P., P.K., B.U., J.P., E.D., U.P., H.B.); Stress and Immunity Lab, Department of Anesthesiology, Ludwig-Maximilians-University Hospital of Munich, Munich, Germany (J.-I.P.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (U.P.); Partner site Munich Heart Alliance, Munich, Germany (U.P.); Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany (S.M., T.K.); and Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Munich, Germany (M.C.).
authors.forename: Marcus
authors.initials: M
authors.lastname: Conrad
authors.affiliation: From the Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany (J.K., H.S., J.-I.P., M.R., M.S., J.H., O.C., K.M.S., J.Q., K.P., P.K., B.U., J.P., E.D., U.P., H.B.); Stress and Immunity Lab, Department of Anesthesiology, Ludwig-Maximilians-University Hospital of Munich, Munich, Germany (J.-I.P.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (U.P.); Partner site Munich Heart Alliance, Munich, Germany (U.P.); Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany (S.M., T.K.); and Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg, Munich, Germany (M.C.). Heike.Beck@med.uni-muenchen.de.
authors.forename: Heike
authors.initials: H
authors.lastname: Beck
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D066026:Endothelial Progenitor Cells / Q000201:enzymology / Q000473:pathology; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D005263:Femoral Artery / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D020022:Genetic Predisposition to Disease; D007249:Inflammation / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D007511:Ischemia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008026:Ligation; D053078:Membrane Potential, Mitochondrial; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D018919:Neovascularization, Physiologic; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D054482:Thioredoxin Reductase 2 / Q000172:deficiency* / Q000235:genetics; D013927:Thrombosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors; D066253:Vascular Remodeling; D014664:Vasodilation
chemical_list: D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D054482:Thioredoxin Reductase 2; C516128:Txnrd2 protein, mouse
keywords: angiogenesis; arteriogenesis; inflammation; reactive oxygen species; thioredoxin reductase 2; thrombosis