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 OlsonGuido Posern, Elisabeth Deindl, Heiner Niemann, Christian Kupatt

Research output: Contribution to journalArticle

43 Scopus citations

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.

Original languageEnglish (US)
Article number3970
JournalNature communications
Volume5
DOIs
StatePublished - Jun 9 2014

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Hinkel, R., Trenkwalder, T., Petersen, B., Husada, W., Gesenhues, F., Lee, S., Hannappel, E., Bock-Marquette, I., Theisen, D., Leitner, L., Boekstegers, P., Cierniewski, C., Müller, O. J., Le Noble, F., Adams, R. H., Weinl, C., Nordheim, A., Reichart, B., Weber, C., ... Kupatt, C. (2014). MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2. Nature communications, 5, [3970]. https://doi.org/10.1038/ncomms4970