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

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Leitner,  Laura
Ullrich, Axel / Molecular Biology, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Hinkel, R., Trenkwalder, T., Petersen, B., Husada, W., Gesenhues, F., Lee, S., et al. (2014). MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2. NATURE COMMUNICATIONS, 5: 3970. doi:10.1038/ncomms4970.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0023-C3F4-D
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.