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MBC in Press, published online ahead of print December 19, 2007
Mol. Biol. Cell 10.1091/mbc.E07-09-0856

A more recent version of this article appeared on March 1, 2008
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Submitted on September 4, 2007
Revised on November 28, 2007
Accepted on December 11, 2007

Coordinated Vascular Endothelial Growth Factor Expression and Signaling During Skeletal Myogenic Differentiation

Brad A. Bryan, Tony E. Walshe, Dianne C. Mitchell, Josh S. Havumaki, Magali Saint-Geniez, Arindel S. Maharaj, Angel E. Maldonado, and Patricia A. D’Amore

Schepens Eye Research Institute, Boston, MA 02114; Departments of Ophthalmology and Pathology, Harvard Medical School, Boston, MA

Monitoring Editor: Richard Hynes

Angiogenesis is largely controlled by hypoxia-driven transcriptional upregulation and secretion of vascular endothelial growth factor (VEGF) and its binding to the endothelial cell tyrosine receptor kinases, VEGFR1 and VEGFR2. Recent expression analysis suggested VEGF is expressed in a cell-specific manner in normoxic adult tissue, however the transcriptional regulation and role of VEGF in these tissues remains fundamentally unknown. In this report we demonstrate that VEGF is coordinately up-regulated during terminal skeletal muscle differentiation. We reveal that this regulation is mediated in part by MyoD homo- and hetero-dimeric transcriptional mechanisms. Serial deletions of the VEGF promoter elucidated a region containing three tandem CANNTG consensus MyoD sites serving as essential sites of direct interaction for MyoD-mediated upregulation of VEGF transcription. VEGF-null embryonic stem (ES) cells exhibited reduced myogenic differentiation compared with wild type ES cells, suggesting that VEGF may serve a role in skeletal muscle differentiation. We demonstrate that VEGFR1 and VEGFR2 are expressed at low levels in myogenic precursor cells and are robustly activated upon VEGF stimulation, and that their expression is coordinately regulated during skeletal muscle differentiation. VEGF stimulation of differentiating C2C12 cells promoted myotube hypertrophy and increased myogenic differentiation, whereas addition of sFlt1, a VEGF inhibitor, resulted in myotube hypotrophy and inhibited myogenic differentiation. We further provide evidence indicating VEGF-mediated myogenic marker expression, mitogenic activity, migration, and prosurvival functions may contribute to increased myogenesis. These data suggest a novel mechanism whereby VEGF is coordinately regulated as part of the myogenic differentiation program, and serves an autocrine function regulating skeletal myogenesis.

Address correspondence to: Patricia A. D’Amore (patricia.damore{at}schepens.harvard.edu)






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