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Gα13 regulates MEF2-dependent gene transcription in endothelial cells: role in angiogenesis

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Abstract

The α subunit of heterotrimeric G13 protein is required for the embryonic angiogenesis (Offermanns et al., Science 275:533–536, 1997). However, the molecular mechanism of Gα13-dependent angiogenesis is not understood. Here, we show that myocyte-specific enhancer factor-2 (MEF2) mediates Gα13-dependent angiogenesis. Our data showed that constitutively activated Gα13Q226L stimulated MEF2-dependent gene transcription. In addition, downregulation of endogenous Gα13 inhibited thrombin-stimulated MEF2-dependent gene transcription in endothelial cells. Both Ca2+/calmodulin-dependent kinase IV (CaMKIV) and histone deacetylase 5 (HDAC5) were involved in Gα13-mediated MEF2-dependent gene transcription. Gα13Q226L also increased Ca2+/calmodulin-independent CaMKIV activity, while dominant negative mutant of CaMKIV inhibited MEF2-dependent gene transcription induced by Gα13Q226L. Furthermore, Gα13Q226L was able to derepress HDAC5-mediated repression of gene transcription and induce the translocation of HDAC5 from nucleus to cytoplasm. Finally, downregulation of endogenous Gα13 and MEF2 proteins in endothelial cells reduced cell proliferation and capillary tube formation. Decrease of endothelial cell proliferation that was caused by the Gα13 downregulation was partially restored by the constitutively active MEF2-VP16. Our studies suggest that MEF2 proteins are an important component in Gα13-mediated angiogenesis.

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Acknowledgments

We thank Drs. M. Cobbs, J. Han, L. Kedes, S. Khochbin, E. Olson, M. Rosner, and J. Xie for providing us with their constructs. This work was supported by National Institutes of Health Grants GM56159 and HL06078 and by a grant from the American Heart Association (to TVY).

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  1. Department of Pharmacology (MC 868), University of Illinois, 835 S. Wolcott Ave., Chicago, IL, 60612, USA

    Guoquan Liu, Jingyan Han, Jasmina Profirovic, Elena Strekalova & Tatyana A. Voyno-Yasenetskaya

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  1. Guoquan Liu
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  2. Jingyan Han
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  3. Jasmina Profirovic
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Correspondence to Tatyana A. Voyno-Yasenetskaya.

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Liu, G., Han, J., Profirovic, J. et al. Gα13 regulates MEF2-dependent gene transcription in endothelial cells: role in angiogenesis. Angiogenesis 12, 1–15 (2009). https://doi.org/10.1007/s10456-008-9123-3

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