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Hinkel, Rabea; Trenkwalder, Teresa; Petersen, Björn; Husada, Wira; Gesenhues, Florian; Lee, Seungmin; Hannappel, Ewald; Bock-Marquette, Ildiko; Theisen, Daniel; Leitner, Laura; Boekstegers, Peter; Cierniewski, Czeslaw; Müller, Oliver J.; le Noble, Ferdinand; Adams, Ralf H.; Weinl, Christine; Nordheim, Alfred; Reichart, Bruno; Weber, Christian; Olson, Eric; Posern, Guido; Deindl, Elisabeth; Niemann, Heiner; Kupatt, Christian (2014): MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2. In: Nature Communications, Vol. 5, 3970
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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 beta 4 (T beta 4), induces MRTF translocation to the nucleus, SRF-activation and CCN1/2 transcription. In a murine ischaemic hindlimb model, MRTF-A or T beta 4 promotes neovascularization, whereas loss of MRTF-A/B or CCN1-function abrogates the T beta 4 effect. We further show that, in ischaemic rabbit hindlimbs, MRTF-A as well as T beta 4 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 T beta 4 (T beta 4tg). We conclude that MRTF-A promotes microvessel growth (via CCN1) and maturation (via CCN2),thereby enabling functional improvement of ischaemic muscle tissue.