MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2

Rabea Hinkel, Teresa Trenkwalder, Björn Petersen, Wira Husada, Florian Gesenhues, Seungmin Lee, Ewald Hannappel, Ildiko Bock-Marquette, Daniel Theisen, Laura Leitner, Peter Boekstegers, Czeslaw Cierniewski, Oliver J. Müller, Ferdinand le Noble, Ralf H. Adams, Christine Weinl, Alfred Nordheim, Bruno Reichart, Christian Weber, Eric Olson, Guido Posern, Elisabeth Deindl, Heiner Niemann and Christian Kupatt ()
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Rabea Hinkel: Medizinische Klinik und Poliklinik I, Klinikum Grosshadern
Teresa Trenkwalder: Medizinische Klinik und Poliklinik I, Klinikum Grosshadern
Björn Petersen: Institute of Farm, Animal Genetics, Friedrich-Loeffler-Institute
Wira Husada: Medizinische Klinik und Poliklinik I, Klinikum Grosshadern
Florian Gesenhues: Medizinische Klinik und Poliklinik I, Klinikum Grosshadern
Seungmin Lee: Medizinische Klinik und Poliklinik I, Klinikum Grosshadern
Ewald Hannappel: Institute for Biochemistry, Friedrich-Alexander University
Ildiko Bock-Marquette: University of Texas Southwestern Medical Center
Daniel Theisen: University Clinic Grosshadern
Laura Leitner: Max Planck Institute of Biochemistry
Peter Boekstegers: Medizinische Klinik und Poliklinik I, Klinikum Grosshadern
Czeslaw Cierniewski: Medical University of Lodz
Oliver J. Müller: Internal Medicine III, University Hospital Heidelberg
Ferdinand le Noble: Angiogenesis and Cardiovascular Pathology, Max-Delbrueck-Center for Molecular Medicine
Ralf H. Adams: Faculty of Medicine, Max Planck Institute for Molecular Biomedicine and University of Muenster
Christine Weinl: Interfaculty Institute for Cell Biology, University of Tuebingen
Alfred Nordheim: Interfaculty Institute for Cell Biology, University of Tuebingen
Bruno Reichart: DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance
Christian Weber: DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance
Eric Olson: University of Texas Southwestern Medical Center
Guido Posern: University Clinic Grosshadern
Elisabeth Deindl: Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians University
Heiner Niemann: Institute of Farm, Animal Genetics, Friedrich-Loeffler-Institute
Christian Kupatt: Medizinische Klinik und Poliklinik I, Klinikum Grosshadern

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4970

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