Hypoxia pp 21-38 | Cite as

Skeletal muscle angiogenesis

A possible role for hypoxia
  • Peter D. Wagner
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 502)


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 words

vascular endothelial growth factor (VEGF) hypoxia inducible factor (HIF-1α) nitric oxide (NO) proton magnetic resonance spectroscopy exercise 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Adhikary G, Premkumar DR, Prabhakar NR. Dual influence of nitric oxide on gene regulation during hypoxia. Adv Exp Med Biol 475:285–292, 2000.PubMedCrossRefGoogle Scholar
  2. 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
  3. 3.
    Benoit H, Jordan M, Wagner H, Wagner PD. Effect of NO, vasodilator prostaglandins and adenosine on skeletal muscle angiogenic growth factor gene expression. J Appl Physiol 86:1513–1518, 1999.PubMedGoogle Scholar
  4. 4.
    Breen EC, Johnson EC, Wagner H, Tseng H-M, Sung LA, Wagner PD. Angiogenic growth factor mRNA responses in muscle to a single bout of exercise. J Appl Physiol 81:355–361,1996.PubMedGoogle Scholar
  5. 5.
    Carmeliet P, Collen D. Molecular basis of angiogenesis. Role of VEGF and VE-cadherin. Ann NY Acad Sci 902:249–264, 2000.PubMedCrossRefGoogle Scholar
  6. 6.
    Dibbens JA, Miller DL, Damert A, Risau W, Vadas MA, Goodall GJ. Hypoxic regulation of vascular endothelial growth factor mRNA stability requires the cooperation of multiple RNA elements. Mol Biol Cell 10:907–919, 1999PubMedGoogle Scholar
  7. 7.
    Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O’Shea KS, Powell-Braxton L, Hillan KJ, Moore MW. Heterozygous embryonic lethality induced by targeted inactivationofthe VEGF gene. Nature 380:439–442, 1996.PubMedCrossRefGoogle Scholar
  8. 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
  9. 9.
    Forsythe JA, Jiang B-H, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL. Activation of vascular endothelial growth factor gene transcription by hypoxia- inducible factor 1. Mol Cell Biol 16:4604–4613, 1996.PubMedGoogle Scholar
  10. 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
  11. 11.
    Gourley M, Williamson JS. Angiogenesis: new targets for the development of anticancer chemotherapies. Curr Pharm Design 6:417–439, 2000.CrossRefGoogle Scholar
  12. 12.
    Griffioen AW, Molema G. Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases and chronic inflammation. Pharmacol Rev 52:237–268, 2000.PubMedGoogle Scholar
  13. 13.
    Groebe K, Thews G. Theoretical analysis of oxygen supply to contracted skeletal muscle. Adv Exp Med Biol 200:495–514, 1986.PubMedCrossRefGoogle Scholar
  14. 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
  15. 15.
    Hogan MC, Bebout DE, Wagner PD. Effect of increased Hb-O2 affinity on VO2max at constant O2 delivery in dog muscle in situ.J Appl Physiol 70:2656–2662, 1991.PubMedGoogle Scholar
  16. 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
  17. 17.
    Honig CR, Gayeski TEJ, Federspiel WJ, Clark A, Jr., Clark P. Muscle O2 gradients from hemoglobin to cytochrome: new concepts, new complexities. Adv Exp Med Biol 169:23–38, 1984.PubMedCrossRefGoogle Scholar
  18. 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
  19. 19.
    Marth JD. Molecular medicine in genetically engineered animals. Recent advances in gene mutagenesis by site-directed recombination. J Clin Invest 97:1999–2002, 1996.PubMedCrossRefGoogle Scholar
  20. 20.
    Mathieu-Costello O, Agey PJ, Wu L, Hang J, Adair TH. Capillary-to-fiber surface ratio in rat fast-twitch hindlimb muscles after chronic electrical stimulation. J Appl Physiol 80:904–909, 1996.PubMedGoogle Scholar
  21. 21.
    Moore GE, Parsons B, Stray-Gundersen J, Painter PL, Brinker KR, Mitchell JH. Uremic myopathy limits aerobic capacity in hemodialysis patients. Am J Kidney Dis 22:277–287, 1993.PubMedGoogle Scholar
  22. 22.
    Noakes TD. Challenging beliefs: ex Africa semper aliquid novi. Med Sci Sports Exerc 29:571–590, 1997.PubMedCrossRefGoogle Scholar
  23. 23.
    Noakes TD. Maximal oxygen uptake: “classical” versus “contemporary” viewpoints: a rebuttal. Med Sci Sports Exerc 30:1381–1398, 1998.PubMedGoogle Scholar
  24. 24.
    O’Leary DS, Dunlap RC, Glover KW. Role of endothelium-derived relaxing factor in hindlimb reactive and active hyperemia in conscious dogs. Am J Physiol 266:R1213–R1219, 1994.PubMedGoogle Scholar
  25. 25.
    Richardson RS, Noyszewski EA, Kendrick KF, Leigh JS, Wagner PD. Myoglobin O2 desaturation during exercise: evidence of limited O2 transport. J Clin Invest 96:1916–1926, 1995.PubMedCrossRefGoogle Scholar
  26. 26.
    Richardson RS, Tagore K, Haseler L, Jordan M, Wagner PD. Increased VO2max with a right shifted Hb-O2 dissociation curve at a constant O2 delivery in dog muscle in situ. J Appl Physiol 84:995–1002, 1998.PubMedGoogle Scholar
  27. 27.
    Roca J, Hogan MC, Story D, Bebout DE, Haab P, Gonzalez R, Ueno O, Wagner PD. Evidence for tissue diffusion limitation of VO2max in normal humans. J Appl Physiol 67:291–299, 1989.PubMedGoogle Scholar
  28. 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
  29. 29.
    Semenza GL, Agani F, Iyer N, Kotch L, Laughner E, Leung S, Yu A. Regulation of cardiovascular development and physiology by hypoxia-inducible factor 1. Ann NY Acad Sci 874:262–268, 1999.PubMedCrossRefGoogle Scholar
  30. 30.
    Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359:843–845, 1992.PubMedCrossRefGoogle Scholar
  31. 31.
    Sullivan MJ, Green HJ, Cobb FR. Skeletal muscle biochemistry and histology in ambulatory patients with long-term heart failure. Circulation 81:518–527, 1990.PubMedCrossRefGoogle Scholar
  32. 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
  33. 33.
    Wagner PD. Determinants of maximal oxygen transport and utilization. Annu Rev Physiol 58:21–50, 1996.PubMedCrossRefGoogle Scholar
  34. 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. 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. 36.
    Weibel ER: The Pathway for Oxygen. Structure and Function in the Mammalian Respiratory System. Cambridge, MA: Harvard University Press, 1984.Google Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Peter D. Wagner
    • 1
  1. 1.Division of Physiology, Department of MedicineUniversity of California, San DiegoLa JollaUSA

Personalised recommendations