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

Item Type:Article
Title:MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2
Creators Name:Hinkel, R. and Trenkwalder, T. and Petersen, B. and Husada, W. and Gesenhues, F. and Lee, S. and Hannappel, E. and Bock-Marquette, I. and Theisen, D. and Leitner, L. and Boekstegers, P. and Cierniewski, C. and Mueller, O.J. and Le Noble, F. and Adams, R.H. and Weinl, C. and Nordheim, A. and Reichart, B. and Weber, C. and Olson, E. and Posern, G. and Deindl, E. and Niemann, H. and Kupatt, C.
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 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.
Keywords:Blood Vessels, Connective Tissue Growth Factor, Cysteine-Rich Protein 61, Genetically Modified Animals, Hibernation, Hindlimb, Ischemia, Myocardial Contraction, Trans-Activators, Animals, Mice, Rabbits, Swine
Source:Nature Communications
ISSN:2041-1723
Publisher:Nature Publishing Group (U.K.)
Volume:5
Page Range:3970
Date:9 June 2014
Official Publication:https://doi.org/10.1038/ncomms4970
PubMed:View item in PubMed

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