Myogenic Akt signaling regulates blood vessel recruitment during myofiber growth.
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.
Takahashi
Akihiro
A
Division of Cardiovascular Research, St. Elizabeth's Medical Center of Boston, School of Medicine, Tufts University, 02135, USA.
Kureishi
Yasuko
Y
Yang
Jiang
J
Luo
Zhengyu
Z
Guo
Kun
K
Mukhopadhyay
Debabrata
D
Ivashchenko
Yuri
Y
Branellec
Didier
D
Walsh
Kenneth
K
D000818:Animals; D001808:Blood Vessels / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D005121:Extremities / Q000098:blood supply; D006801:Humans; D006984:Hypertrophy; D007511:Ischemia / Q000503:physiopathology; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011817:Rabbits; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt