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, Patricia A. D'Amore

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

Angiogenesis is largely controlled by hypoxia-driven transcriptional up-regulation and secretion of vascular endothelial growth factor (VEGF) and its binding to the endothelial cell tyrosine receptor kinases, VEGFR1 and VEGFR2. Recent expression analysis suggests that 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 up-regulation 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.

Original languageEnglish (US)
Pages (from-to)994-1006
Number of pages13
JournalMolecular Biology of the Cell
Volume19
Issue number3
DOIs
StatePublished - Mar 2008
Externally publishedYes

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Vascular Endothelial Growth Factor A
Skeletal Muscle
Muscle Development
Skeletal Muscle Fibers
Embryonic Stem Cells
Up-Regulation
Receptor Protein-Tyrosine Kinases
Hypertrophy
Endothelial Cells

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Coordinated vascular endothelial growth factor expression and signaling during skeletal myogenic differentiation. / Bryan, Brad A.; Walshe, Tony E.; Mitchell, Dianne C.; Havumaki, Josh S.; Saint-Geniez, Magali; Maharaj, Arindel S; Maldonado, Angel E.; D'Amore, Patricia A.

In: Molecular Biology of the Cell, Vol. 19, No. 3, 03.2008, p. 994-1006.

Research output: Contribution to journalArticle

Bryan, BA, Walshe, TE, Mitchell, DC, Havumaki, JS, Saint-Geniez, M, Maharaj, AS, Maldonado, AE & D'Amore, PA 2008, 'Coordinated vascular endothelial growth factor expression and signaling during skeletal myogenic differentiation', Molecular Biology of the Cell, vol. 19, no. 3, pp. 994-1006. https://doi.org/10.1091/mbc.E07-09-0856
Bryan, Brad A. ; Walshe, Tony E. ; Mitchell, Dianne C. ; Havumaki, Josh S. ; Saint-Geniez, Magali ; Maharaj, Arindel S ; Maldonado, Angel E. ; D'Amore, Patricia A. / Coordinated vascular endothelial growth factor expression and signaling during skeletal myogenic differentiation. In: Molecular Biology of the Cell. 2008 ; Vol. 19, No. 3. pp. 994-1006.
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