TY - JOUR
T1 - MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2
AU - Hinkel, Rabea
AU - Trenkwalder, Teresa
AU - Petersen, Björn
AU - Husada, Wira
AU - Gesenhues, Florian
AU - Lee, Seungmin
AU - Hannappel, Ewald
AU - Bock-Marquette, Ildiko
AU - Theisen, Daniel
AU - Leitner, Laura
AU - Boekstegers, Peter
AU - Cierniewski, Czeslaw
AU - Müller, Oliver J.
AU - Le Noble, Ferdinand
AU - Adams, Ralf H.
AU - Weinl, Christine
AU - Nordheim, Alfred
AU - Reichart, Bruno
AU - Weber, Christian
AU - Olson, Eric
AU - Posern, Guido
AU - Deindl, Elisabeth
AU - Niemann, Heiner
AU - Kupatt, Christian
PY - 2014/6/9
Y1 - 2014/6/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84902248750&partnerID=8YFLogxK
U2 - 10.1038/ncomms4970
DO - 10.1038/ncomms4970
M3 - Article
C2 - 24910328
AN - SCOPUS:84902248750
SN - 2041-1723
VL - 5
JO - Nature Communications
JF - Nature Communications
M1 - 3970
ER -