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Molecular and Cellular Biology, July 2002, p. 4803-4814, Vol. 22, No. 13
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.13.4803-4814.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Myogenic Akt Signaling Regulates Blood Vessel Recruitment during Myofiber Growth

Akihiro Takahashi,1 Yasuko Kureishi,1 Jiang Yang,1,2,3 Zhengyu Luo,1 Kun Guo,4 Debabrata Mukhopadhyay,5,6 Yuri Ivashchenko,4 Didier Branellec,7 and Kenneth Walsh1,2,3*

Division of Cardiovascular Research, St. Elizabeth's Medical Center of Boston,1 Program in Cell, Molecular, and Developmental Biology, Sackler School of Biomedical Sciences, School of Medicine, Tufts University, Boston, Massachusetts 02135,3 Molecular Cardiology, Whitaker Cardiovascular Institute, School of Medicine, Boston University, Boston, Massachusetts 02118,2 Cardiovascular Disease Group, Aventis Pharma, Frankfurt 65926, Germany,4 Department of Pathology, Beth Israel Deaconess Medical Center,5 Department of Pathology, Harvard Medical School, Boston, Massachusetts 02215,6 Aventis Gencell, 94403 Vitry sur Seine, France7

Received 22 January 2002/ Returned for modification 28 February 2002/ Accepted 25 March 2002

Blood vessel recruitment is an important feature of normal tissue growth. Here, we examined the role of Akt signaling in coordinating angiogenesis with skeletal muscle hypertrophy. Hypertrophy of C2C12 myotubes in response to insulin-like growth factor 1 or insulin and dexamethasone resulted in a marked increase in the secretion of vascular endothelial growth factor (VEGF). Myofiber hypertrophy and hypertrophy-associated VEGF synthesis were specifically inhibited by the transduction of a dominant-negative mutant of the Akt1 serine-threonine protein kinase. Conversely, transduction of constitutively active Akt1 increased myofiber size and led to a robust induction of VEGF protein production. Akt-mediated control of VEGF expression occurred at the level of transcription, and the hypoxia-inducible factor 1 regulatory element was dispensable for this regulation. The activation of Akt1 signaling in normal mouse gastrocnemius muscle was sufficient to promote myofiber hypertrophy, which was accompanied by an increase in circulating and tissue-resident VEGF levels and high capillary vessel densities at focal regions of high Akt transgene expression. In a rabbit hind limb model of vascular insufficiency, intramuscular activation of Akt1 signaling promoted collateral and capillary vessel formation and an accompanying increase in limb perfusion. These data suggest that myogenic Akt signaling controls both fiber hypertrophy and angiogenic growth factor synthesis, illustrating a mechanism through which blood vessel recruitment can be coupled to normal tissue growth.

* Corresponding author. Mailing address: Molecular Cardiology/CVI, Boston University School of Medicine, 715 Albany St., W-611, Boston, MA 02118. Phone: (617) 414-2392. Fax: (617) 414-2391. E-mail: kwalsh{at}world.std.com.

Molecular and Cellular Biology, July 2002, p. 4803-4814, Vol. 22, No. 13
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.13.4803-4814.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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