title: MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2.
abstract: Gradual occlusion of coronary arteries may result in reversible loss of cardiomyocyte function (hibernating myocardium), which is amenable to therapeutic neovascularization. The role of myocardin-related transcription factors (MRTFs) co-activating serum response factor (SRF) in this process is largely unknown. Here we show that forced MRTF-A expression induces CCN1 and CCN2 to promote capillary proliferation and pericyte recruitment, respectively. We demonstrate that, upon G-actin binding, thymosin ß4 (Tß4), induces MRTF translocation to the nucleus, SRF-activation and CCN1/2 transcription. In a murine ischaemic hindlimb model, MRTF-A or Tß4 promotes neovascularization, whereas loss of MRTF-A/B or CCN1-function abrogates the Tß4 effect. We further show that, in ischaemic rabbit hindlimbs, MRTF-A as well as Tß4 induce functional neovascularization, and that this process is inhibited by angiopoietin-2, which antagonizes pericyte recruitment. Moreover, MRTF-A improves contractile function of chronic hibernating myocardium of pigs to a level comparable to that of transgenic pigs overexpressing Tß4 (Tß4tg). We conclude that MRTF-A promotes microvessel growth (via CCN1) and maturation (via CCN2), thereby enabling functional improvement of ischaemic muscle tissue.
authors.affiliation: 1] Medizinische Klinik und Poliklinik I, Klinikum Grosshadern, 81377 Munich, Germany [2] DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, 80802 München, Germany [3].
authors.forename: Rabea
authors.initials: R
authors.lastname: Hinkel
authors.affiliation: 1] Medizinische Klinik und Poliklinik I, Klinikum Grosshadern, 81377 Munich, Germany [2] DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, 80802 München, Germany [3] Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians University, 81377 München, Germany [4].
authors.forename: Teresa
authors.initials: T
authors.lastname: Trenkwalder
authors.affiliation: Institute of Farm, Animal Genetics, Friedrich-Loeffler-Institute, 31535 Neustadt a.Rbge, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Petersen
authors.affiliation: Medizinische Klinik und Poliklinik I, Klinikum Grosshadern, 81377 Munich, Germany.
authors.forename: Wira
authors.initials: W
authors.lastname: Husada
authors.affiliation: Medizinische Klinik und Poliklinik I, Klinikum Grosshadern, 81377 Munich, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Gesenhues
authors.affiliation: Medizinische Klinik und Poliklinik I, Klinikum Grosshadern, 81377 Munich, Germany.
authors.forename: Seungmin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Institute for Biochemistry, Friedrich-Alexander University, 91054 Erlangen, Germany.
authors.forename: Ewald
authors.initials: E
authors.lastname: Hannappel
authors.affiliation: 1] Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA [2] Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, H-7624 Pécs, Hungary.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Bock-Marquette
authors.affiliation: Department of Clinical Radiology, University Clinic Grosshadern, 81377 Munich, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Theisen
authors.affiliation: Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Leitner
authors.affiliation: Medizinische Klinik und Poliklinik I, Klinikum Grosshadern, 81377 Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Boekstegers
authors.affiliation: Department of Molecular and Medical Biophysics, Medical University of Lodz, Lodz 93-232, Poland.
authors.forename: Czeslaw
authors.initials: C
authors.lastname: Cierniewski
authors.affiliation: 1] Department of Cardiology, Internal Medicine III, University Hospital Heidelberg, 69120 Heidelberg, Germany [2] DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany.
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Müller
authors.affiliation: 1] Angiogenesis and Cardiovascular Pathology, Max-Delbrueck-Center for Molecular Medicine, 13092 Berlin, Germany [2] DZHK (German Center for Cardiovascular Research), partner site Max-Delbruek-Center, 13092 Berlin, Germany.
authors.forename: Ferdinand
authors.initials: F
authors.lastname: le Noble
authors.affiliation: Department of Tissue Morphogenesis, Faculty of Medicine, Max Planck Institute for Molecular Biomedicine and University of Muenster, 48149 Muenster, Germany.
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Adams
authors.affiliation: Department of Molecular Biology, Interfaculty Institute for Cell Biology, University of Tuebingen, 72076 Tuebingen, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Weinl
authors.affiliation: Department of Molecular Biology, Interfaculty Institute for Cell Biology, University of Tuebingen, 72076 Tuebingen, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Nordheim
authors.affiliation: 1] DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, 80802 München, Germany [2] Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians University, 81377 München, Germany.
authors.forename: Bruno
authors.initials: B
authors.lastname: Reichart
authors.affiliation: 1] DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, 80802 München, Germany [2] Institute for Cardiovascular Prevention, Ludwig-Maximilians University, 80336 München,, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Olson
authors.affiliation: 1] Department of Clinical Radiology, University Clinic Grosshadern, 81377 Munich, Germany [2] Institute of Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, 06114 Halle (Saale), Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Posern
authors.affiliation: Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians University, 81377 München, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Deindl
authors.affiliation: Institute of Farm, Animal Genetics, Friedrich-Loeffler-Institute, 31535 Neustadt a.Rbge, Germany.
authors.forename: Heiner
authors.initials: H
authors.lastname: Niemann
authors.affiliation: 1] Medizinische Klinik und Poliklinik I, Klinikum Grosshadern, 81377 Munich, Germany [2] DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, 80802 München, Germany [3] Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians University, 81377 München, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kupatt
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001808:Blood Vessels / Q000254:growth & development* / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D055515:Cysteine-Rich Protein 61 / Q000378:metabolism*; D006605:Hibernation; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D009200:Myocardial Contraction; D011817:Rabbits; D013552:Swine; D015534:Trans-Activators / Q000502:physiology*
chemical_list: C491850:CCN1 protein, mouse; C526318:CCN2 protein, mouse; D055515:Cysteine-Rich Protein 61; C511173:Mrtfa protein, mouse; D015534:Trans-Activators; D055513:Connective Tissue Growth Factor