Skeletal muscle angiogenesis
Skeletal muscle is one of the most plastic tissues in the body. Repeated exercise causes several muscle adaptations, among which the development of additional capillaries (angiogenesis) is prominent. Conversely, inactivity and some chronic diseases result in loss of muscle capillaries. Since (endurance) exercise depends on adequate O2 supply, it is reasonable to hypothesize that hypoxia occurring within muscle during exercise may provide the stimulus to angiogenesis. However, there are other potential stimuli including physical effects of increased muscle blood flow, or of muscle contraction; release of molecules such as NO that could transcriptionally activate angiogenic growth factors; and perhaps changes in the biochemical milieu of the muscle cell such as acidosis. This brief review will address evidence collected to date mostly at the molecular biological level that does in fact implicate reduced intracellular Po2 as a major stimulus to the angiogenic process resulting from exercise. In particular, it is shown that VEGF message and protein are increased in muscle with exercise, more so in hypoxia, and that HIF-1α correlates with VEGF as would be expected if hypoxia were the major stimulus. In addition, we show that muscle intracellular PO2 falls to very low levels during exercise (3–4 Torr), providing a degree of hypoxia compatible with a strong role for low Po2 in angiogenic growth factor response. However, the definitive experiments using acute gene manipulation to establish a cause and effect relationship between hypoxia and muscle angiogenesis remain to be performed.
Key wordsvascular endothelial growth factor (VEGF) hypoxia inducible factor (HIF-1α) nitric oxide (NO) proton magnetic resonance spectroscopy exercise
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- 2.Bebout DE, Hogan MC, Hempleman SC, Wagner PD. Effects of training and immobilization on VO2 and DO2 in dog gastrocnemius muscle in situ. J Appl Physiol 74:1697–1703, 1993.Google Scholar
- 8.Ferrara N, Houck KA, Jakeman LB, Winer J, Leung DW. The vascular endothelial growth factor family of polypeptides. J Cell Biol 47:211–218, 1991.Google Scholar
- 10.Gavin TP, Wagner PD. Effects of exercise and nitric oxide synthase inhibition on skeletal muscle VEGF receptor mRNA. Am J Physiol (Heart Circ Physiol), submitted for publication, 2001.Google Scholar
- 14.Hepple RT, Hogan MC, Stary CM, Bebout DE, Mathieu-Costello O, Wagner PD. Structural basis of muscle O2 diffusing capacity: evidence from muscle function in situ. J Appl Physiol 88:560–566, 2000.Google Scholar
- 16.Homma S, Gavin TP, Mathieu-Costello O, Wagner PD: Influence of chronic nitric oxide inhibition on muscle capillarization. The Physiologist 43:350, 2000.(Abstract)Google Scholar
- 18.Krogh A. The number and distribution of capillaries in muscle with calculations of the pressure head necessary for supplying the tissue. J Physiol (Lond) 52:409–415, 1919.Google Scholar
- 28.Saltin B, Gollnick PD: Skeletal muscle adaptability: significance for metabolism and performance. In: Handbook of Physiology. Skeletal Muscle, edited by Peachy, et al. Bethesda, MD: Am.Physiol.Soc, 1983, p. 555–631.Google Scholar
- 32.Tang K, Breen EC, Wagner H, Chen Q, Brutsaert TD, Gassmann M, Wagner PD. Relationship between HIF and VEGF responses to moderate hypoxia and to sciatic nerve stimulation in rat gastrocnemius muscle. Am J Physiol Reg Int Comp Physiol, submitted for publication, 2001.Google Scholar
- 34.Wagner PD, Hoppeler H, Saltin B: Determinants of maximal oxygen uptake. In: The Lung: Scientific Foundations, edited by Crystal RG, West JB, Barnes PJ, Cherniack NS, Weibel ER. New York: Raven Press, 1991, p. 1585–1593.Google Scholar
- 35.Wagner PD, Masanes F, Wagner H, Sala E, Miro O, Campistol JM, Marrades RM, Casademont J, Torregrosa JV, Roca J. Muscle angiogenic growth factor gene responses to exercise in chronic renal failure. Am J Physiol Reg Int Comp Physiol, submitted for publication, 2001.Google Scholar
- 36.Weibel ER: The Pathway for Oxygen. Structure and Function in the Mammalian Respiratory System. Cambridge, MA: Harvard University Press, 1984.Google Scholar