期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 22, 期 13, 页码 4803-4814出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.22.13.4803-4814.2002
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资金
- NHLBI NIH HHS [HL-50692] Funding Source: Medline
- NIAMS NIH HHS [R01 AR040197, AR-40197] Funding Source: Medline
- NIA NIH HHS [R37 AG015052, AG-17241, AG-15052, R01 AG017241, R01 AG015052] Funding Source: Medline
- NICHD NIH HHS [HD-23681, P01 HD023681] Funding Source: Medline
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 I 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.
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