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Nat Commun. 2014 Jun 9;5:3970. doi: 10.1038/ncomms4970.

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

Author information

1
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].
2
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].
3
Institute of Farm, Animal Genetics, Friedrich-Loeffler-Institute, 31535 Neustadt a.Rbge, Germany.
4
Medizinische Klinik und Poliklinik I, Klinikum Grosshadern, 81377 Munich, Germany.
5
Institute for Biochemistry, Friedrich-Alexander University, 91054 Erlangen, Germany.
6
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.
7
Department of Clinical Radiology, University Clinic Grosshadern, 81377 Munich, Germany.
8
Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
9
Department of Molecular and Medical Biophysics, Medical University of Lodz, Lodz 93-232, Poland.
10
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.
11
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.
12
Department of Tissue Morphogenesis, Faculty of Medicine, Max Planck Institute for Molecular Biomedicine and University of Muenster, 48149 Muenster, Germany.
13
Department of Molecular Biology, Interfaculty Institute for Cell Biology, University of Tuebingen, 72076 Tuebingen, Germany.
14
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.
15
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.
16
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA.
17
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.
18
Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians University, 81377 München, Germany.
19
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.

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.

PMID:
24910328
DOI:
10.1038/ncomms4970
[Indexed for MEDLINE]
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