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

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.; Mueller, O.J.; le Noble, F.; Adams, R.H.; Weinl, C.; Nordheim, A.; Reichart, B.; Weber, C.; Olson, E.; Posern, G.; Deindl, E.; Niemann, H.; Kupatt, C.

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

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Item Type:	Article
Title:	MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2
Creators Name:	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., Mueller, O.J., le Noble, F., Adams, R.H., Weinl, C., Nordheim, A., Reichart, B., Weber, C., Olson, E., Posern, G., Deindl, E., 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
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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