Skeletal muscle capillarity during hypoxia: VEGF and its activation.
Long-term exposure of humans and many mammals to hypoxia leads to the activation of several cellular mechanisms within skeletal muscles that compensate for a limited availability of cellular oxygen. One of these cellular mechanisms is to increase the expression of a subset of hypoxia-inducible genes, including the expression of vascular endothelial growth factor (VEGF). The VEGF promoter contains a hypoxic response element (HRE) that can bind the transcription factor, hypoxia-inducible factor-1alpha; (HIF-1alpha), and initiate transcriptional activation of the VEGF gene. VEGF gene expression is critically important for skeletal muscle angiogenesis and VEGF gene deletion in the mouse has been shown to greatly reduce skeletal muscle capillarity. However, HIF-1alpha-dependent transcriptional activation of the VEGF gene may not be the only signaling pathway that leads to increased or maintained VEGF levels under conditions of acute or long-term hypoxia. Additional mechanisms, induced during hypoxic exposure that could signal skeletal muscle VEGF activation include inflammation, possibly linked to reactive O(2) species generation, or a change in cellular energy status as reflected by AMP kinase activity. These pathways may provide quite different mechanisms for VEGF upregulation in the context of muscular activity during long-term exposure to a hypoxic environment such as occurs at high altitude. This review will accordingly discuss the potential cellular signals or stimuli resulting from hypoxic exposure that could increase myocyte VEGF expression. These cellular signals include 1) a decrease in intracellular P(O(2)), 2) skeletal muscle inflammation, associated cytokines and oxidative stress, and 3) an increase in AMP kinase activity and adenosine accompanying a reduction in cellular energy potential.
Breen
Ellen
E
Department of Medicine, University of California at San Diego, La Jolla, CA 92093-0623, USA. ebreen@ucsd.edu
Tang
Kechun
K
Olfert
Mark
M
Knapp
Amy
A
Wagner
Peter
P
D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D002196:Capillaries / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000097:blood*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D008322:Mammals; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000378:metabolism*; D010101:Oxygen Consumption; D012039:Regional Blood Flow; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D016228:Endothelial Growth Factors; D042461:Vascular Endothelial Growth Factor A