, Volume 8, Issue 3, pp 263–271 | Cite as

Angiogenesis during exercise and training

  • Colin M. Bloor


In this review the factors involved in angiogenesis are discussed in their various roles in initiating angiogenesis and inducing changes in the extracellular matrix to facilitate sprouting angiogenesis which is a major part of the angiogenesis seen in exercise and exercise training. A key role in angiogenesis is played by vascular endothelial growth factor (VEGF). The regulation of blood vessel growth to match the needs of the tissue depends on the control of VEGF production through changes in the stability of its mRNA and in its rate of transcription. The detailed studies describing its characteristics and its upregulation in acute exercise are presented along with a brief overview of the changes in the extracellular matrix that facilitate sprouting angiogenesis that occurs in response to exercise and training. Although the mechanisms involved in the growth and remodeling of arterioles and larger vessels are less detailed some recent studies have provided new insights. These are presented here to show a relationship between capillary development and arteriolar growth or remodeling in exercise training that raises questions to be addressed in future studies.

Key words

blood vessel growth cardiac muscle growth factors skeletal muscle sprouting angiogenesis vascular adaptation vascular remodeling VEGF 


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  1. 1.
    Folkman J, Shing Y (1992). Angiogenesis. J Biol Chem 267:10931–4PubMedGoogle Scholar
  2. 2.
    White FC, Bloor CM, McKirnan MD et al. (1998). Exercise training in swine promotes growth of arteriolar bed and capillary angiogenesis in heart. J Appl Physiol 85: 1160–8PubMedGoogle Scholar
  3. 3.
    Tomanek RJ (1990). Response of the coronary vasculature to myocardial hypertrophy. J Am Coll Cardiol 15: 528–33PubMedCrossRefGoogle Scholar
  4. 4.
    Laughlin MH, Overholser KA, Bhatte MJ (1989). Exercise training increases coronary transport reserve in miniature swine. J Appl Physiol 67: 1140–9PubMedGoogle Scholar
  5. 5.
    Laughlin MH, Tomanek RJ. (1987).. Myocardial capillarity and maximal capillary diffusion capacity in exercise-trained dogs. J Appl Physiol 63: 1481–6PubMedGoogle Scholar
  6. 6.
    Laughlin MH, McAllister RM (1992). Exercise training-induced coronary vascular adaptation. J Appl Physiol 73: 2209–25PubMedGoogle Scholar
  7. 7.
    Brown MD, Hudlicka O (2003). Modulation of physiological angiogenesis in skeletal muscle by mechanical forces: involvement of VEGF and metalloproteinases. Angiogenesis 6:1–14CrossRefPubMedGoogle Scholar
  8. 8.
    Buschmann I, Heil M, Jost M et al. (2003). Influence of inflammatory cytokines on arteriogenesis. Microcirculation 10: 371–79CrossRefPubMedGoogle Scholar
  9. 9.
    Conway EM, Callen D, Carmeliet P. (2001). Molecular mechanisms of blood vessel growth. Cardiovasc Res 49: 507–21CrossRefPubMedGoogle Scholar
  10. 10.
    Djonov V., Baum O, Burri P II. (2003). Vascular remodeling by intussusceptive angiogenesis. Cell Tissue Res 314: 107–17CrossRefPubMedGoogle Scholar
  11. 11.
    Gustafsson T, Kraus WE. (2001). Exercise-induced angiogenesis-related growth and transcription factors in skeletal muscle and their modification in muscle pathology. Front Biosci 6: 75- 89CrossRefGoogle Scholar
  12. 12.
    Helisch A, Schaper S. (2003). Arteriogenesis: the development and growth of collateral arteries. Microcirculation 10: 83–97CrossRefPubMedGoogle Scholar
  13. 13.
    Hudlicka O. (1998). Is physiological angiogenesis in skeletal muscle regulated by changes in microcirculation?. Microcirculation 5: 7–23CrossRefPubMedGoogle Scholar
  14. 14.
    Resnick N, Einav S, Chen-Konak L et al. (2003). Hemodynamic forces as a stimulus for arteriogenesis. Endothelium 10: 197–206PubMedCrossRefGoogle Scholar
  15. 15.
    Prior BM, Yang HT, Terjung RL. (2004). What makes vessels grow with exercise training?. J Appl Physiol 97: 1119–28CrossRefPubMedGoogle Scholar
  16. 16.
    Egginton S, Zhou AL, Brown MD et al. (2001). Unorthodox angiogenesis in skeletal muscle. Cardiovasc Res 49: 2025–32CrossRefGoogle Scholar
  17. 17.
    Hansen-Smith FM, Hudlicka O, Egginton S. (1996). In vivo angiogenesis in adult rat skeletal muscle: early changes in capillary network architecture and ultrastructure. Cell Tissue Res 286: 123–36CrossRefPubMedGoogle Scholar
  18. 18.
    Haas TL, Milkiewicz M, Davis SJ et al. (2000). Matrix metalloproteinase activity is required for activity-induced angiogenesis in rat skeletal muscle. Am J Physiol Heart Circ Physiol 279: H1540–47PubMedGoogle Scholar
  19. 19.
    Goto F, Goto K, Weindel K et al. (1993). Synergistic effects of vascular endothelial growth factor and basic fibroblast growth factor on the proliferation and cord formation of bovine capillary endothelial cells within collagen gels. Lab Invest 69: 508–17PubMedGoogle Scholar
  20. 20.
    Matsumoto T, Claesson-Welsh L. (2001). VEGF receptor signal transduction. Sci STKE 2001: RE21PubMedCrossRefGoogle Scholar
  21. 21.
    Cucina A, Borrelli V, Randone B et al. (2003). Vascular endothelial growth factor increases the migration and proliferation of smooth muscle cells through the mediation of growth factors released by endothelial cells. J Surg Res 109: 16–23CrossRefPubMedGoogle Scholar
  22. 22.
    Bernatchez PN, Soker S, Sirois MG. (1999). Vascular endothelial growth factor effect on endothelial cell proliferation, migration and platelet-activating factor synthesis is Flk-l-dependent. J Biol Chem 274: 31047–54CrossRefPubMedGoogle Scholar
  23. 23.
    Gills H, Kowalski J, Li B et al. (2001). Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1 and) and KDR (VEGFR-2). A reassessment using novel receptor specific vascular endothelial growth factor mutants. J Biol Chem 276: 3222–30CrossRefPubMedGoogle Scholar
  24. 24.
    Waltenberger J, Claesson-Welsh L, Siegbahn A et al. (1995). Different signal transduction properties of KDR and Flt-l, two receptors for vascular endothelial growth. J Biol Chem 269: 26988–95Google Scholar
  25. 25.
    Wu LW, Mayo LD, Dunbar JD et al. (2000). Utilization of distict signaling pathways by receptors for vascular endothelial cell growth. J Biol Chem 275: 5096–103CrossRefPubMedGoogle Scholar
  26. 26.
    Amaral SL, Linderman RI, Morse MM, Greene AS. (2001). Angiogenesis induced by electrical stimulation is mediated by angiotensin II and VEGF. Microcirculation 8: 57–67CrossRefPubMedGoogle Scholar
  27. 27.
    Milkiewicz M, Hudlicka O, Verhaeg J et al. (2003). Differential expression of Elk-I and Flt-1 in rat skeletal muscle in response to chronic ischemia: favourable effect of muscle activity. Clin Sci (Colch) 105: 473–82CrossRefGoogle Scholar
  28. 28.
    Babaei S, Teichert-Knliszewska K, Monge JC et al. (1999). Role of nitric oxide in the angiogenic response to basic fibroblastic growth factor. Circ Res 85: 1007–15Google Scholar
  29. 29.
    Gustafsson T, Puntschart A, Kaijser L et al. (1999). Exercise-induced expression of angiogenesis-related transcription and growth factors in human skeletal muscle. Am J Physiol Heart Circ Physiol 276: H679–85Google Scholar
  30. 30.
    Richardson RS, Wagner H, Mudaliar SR et al. (1999). Human VEGF gene expression in skeletal muscle: effect of acute normoxic and hypoxic exercise. Am J Physiol Heart Circ Physiol 277: H2247–52Google Scholar
  31. 31.
    Deschenes MR, Ogilvie RW (1999). Exercise stimulates neovascularization in occluded muscle without affecting bFGF content. Med Sci Sports 31: 1599–1604Google Scholar
  32. 32.
    Egginton S, Hudlicka O, Brown MD et al. (1998). Capillary growth in relation blood flow and performance in overloaded rat skeletal muscle. J Appl Physiol 85: 2025–32PubMedGoogle Scholar
  33. 33.
    Gale NW, Yancopoulos GD. (1999). Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins and ephrins in vascular development. Genes Dev 13: 1055–66PubMedGoogle Scholar
  34. 34.
    Rivills I. Milkiewicz M, Boyd P et al. (2002). Differential involvement of MMP-2 and VEGF during muscle stretch vs shear stress-induced angiogenesis. Am J Physiol Heart Circ Physiol 283: H430–38Google Scholar
  35. 35.
    Hansen-Smith SF, Egginton S, Zhou AL et al. (2001). Growth of arterioles precedes that of capillaries in stretch-induced angiogenesis in skeletal muscle. Microvasc Res 62: 1–14CrossRefPubMedGoogle Scholar
  36. 36.
    Zhou AL, Egginton S, Brown MID et al. (1998). Capillary growth in overloaded, hypertrophic adult rat skeletal muscle: an ultrastructural study. Anat Rec 252: 49–63CrossRefPubMedGoogle Scholar
  37. 37.
    Zhou AL, Egginton S, Hudlicka O et al. (1998). Internal division of capillaries in rat skeletal muscle in respone to chronic vasodilator treatment with α1-antagonist prazosin. Cell Tissue Res 293: 293–303CrossRefPubMedGoogle Scholar
  38. 38.
    Shwceiki D, Itin A, Softer D et al. (1992). Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359: 843–845CrossRefPubMedGoogle Scholar
  39. 39.
    Gustafsson T, Puntschart A, Sundberg CJ et al. (1999). Related expression of vascular endothelial growth factor and hypoxia-inducible factor-1 mRNA in human skeletal muscle. Acta Physiol Scand 165: 335–36CrossRefPubMedGoogle Scholar
  40. 40.
    Jiang BH, Semenza GL, Hugo CB et al. (1996). Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2tension. Am J Physiol Cell Physiol 271: C1172–80Google Scholar
  41. 41.
    Brown MD. (2003). Exercise and coronary vascular remodeling in the healthy heart. Experimental Physiology 88.5: 645–58CrossRefPubMedGoogle Scholar
  42. 42.
    Annex BII, Torgan CE, Lin PMA et al. (1998). Induction and maintenance of increased VEGF protein by chronic nerve stimulation in skeletal muscle. Am J Physiol Heart Circ Physiol 274: H860–67Google Scholar
  43. 43.
    Hang J, Kong L, Gu JW et al. (1995). VEGF gene expression is upregulated in electrically stimulated rat skeletal muscle. Am J Physiol Heart Physiol 269: H827–34Google Scholar
  44. 44.
    Breen EC, Johnson EC, Wagner H et al. (1996). Angiogenic growth factor mRNA responses in muscle to a single bout of exercise. J Appl Physiol 81: 355–61PubMedGoogle Scholar
  45. 45.
    Gustafsson T, Bodin K, Sylven C et al. (2001). Increased expression of VEGF following exercise training in patients with heart failure. Eur J Clin Invest 31: 362–66CrossRefPubMedGoogle Scholar
  46. 46.
    Gustafsson T, Knutssun A, Puntschart A et al. (2002). Increased expression of vascular endothelial growth factor in human skeletal muscle in response to short-term one-legged exercise training. Pflugers Arch 444: 752–759CrossRefPubMedGoogle Scholar
  47. 47.
    Gavin TP, Robinson CB, Yeager RC et al. (2004). Angiogenic growth factor response to acute systemic exercise in human skeletal muscle. J Appl Physiol 96: 19–24CrossRefPubMedGoogle Scholar
  48. 48.
    Hoffner L, Nielsen JJ, Langberg H et al. (2003). Exercise but not prostanoids enhance levels of vascular endothelial growth factor and other proliferative agents in humans skeletal muscle interstitium. J Physiol 550: 217–25CrossRefPubMedGoogle Scholar
  49. 49.
    Hiscock N, Fischer CP, Pilegaard H et al. (2003). Vascular endothelial growth mRNA expression and arteriovenous balance in response to prolonged, submaximal exercise in humans. Am J Physiol Heart Circ Physiol 285: H1759–63PubMedGoogle Scholar
  50. 50.
    Amaral SL, Papanek PE, Greene AS. (2001). Angiotensin II and VEGF are involved in angiogenesis induced by short-term exercise training. Am J Physiol Heart Circ Physiol 281: H1163–69PubMedGoogle Scholar
  51. 51.
    Lloyd PG, Prior BM, Yang HT et al. (2003). Angiogenic growth factor expression in rat skeletal muscle in response to exercise training. Am J Physiol Heart Circ Physiol 284: H1668–78PubMedGoogle Scholar
  52. 52.
    Gavin TP, Spector DA, Wagner H et al. (2001). Effect of captopril on skeletal muscle angiogenic growth factor responses to exercise. J Appl Physiol 90: 1690–97Google Scholar
  53. 53.
    Gavin TP, Wagner PD. (2002). Attenuation of the exercise-induced increase in skeletal muscle Flt-1 mRNA by nitric oxide synthase inhibition. Acta Physiol Scand 175: 201–9CrossRefPubMedGoogle Scholar
  54. 54.
    Vassilakopoulas T, Deckman G, Kebbewar M et al. (2003). Regulation of nitric oxide production in limb and ventilatory muscles during chronic exercise training. Am J Physiol Lung Cell Mol Physiol 253: L452–57Google Scholar
  55. 55.
    Morbidelli L, Chang CH, Douglas JG et al. (1996). Nitric oxide mediates mitogenic effect of VEGF on coronary venular endothelium. Am J Physiol Heart Circ Physiol 270: H411–15Google Scholar
  56. 56.
    Kraus RM, Stallings HW III, Yeager RC et al. (2004). Circulating plasma VEGF response to exercise in sedentary and endurance-trained men. J Appl Physiol 96: 1445–450CrossRefPubMedGoogle Scholar
  57. 57.
    Gavin TP, Wagner PD. (2001). Effect of short-term exercise training on angiogenic growth factor gene response in rats. J Appl Physiol 90: 1219–126PubMedGoogle Scholar
  58. 58.
    Richardson RS, Wagner H, Mudaliar SRD et al. (2000). Exercise adaptation attenuates VEGF gene expression in human skeletal muscle. Am J Physiol Heart Circ Physiol 279: H772–78PubMedGoogle Scholar
  59. 59.
    Laughlin MH, Korthuis RJ, Duncker DJ et al. Control of blood flow to cardiac and skeletal muscle during exercise. In: Handbook of Physiology. Exercise, Regulation and Integration of Multiple Systems. Bethesda: Am Physiol Soc 1996; 705–69Google Scholar
  60. 60.
    Mackie BG, Terjung RL. (1983). Influence of training on blood flow to different skeletal muscle fiber types. J Appl Physiol 55: 1072–78PubMedGoogle Scholar
  61. 61.
    Tronc F, Wassef M, Esposito B et al. (1996). Role of NO in flow-induced remodeling of the rabbit common carotid artery. Arterioscler Thromb Vasc Biol 16: 1256–62PubMedGoogle Scholar
  62. 62.
    Hounker M, Schmid A, Schmidt-Trucksass A et al. (2003). Size and blood flow of central and peripheral arteries in highly trained able-bodied and disabled athletes. J Appl Physiol 95: 685PubMedGoogle Scholar
  63. 63.
    Carrow RE, Brown RE, Van Hess WD. (1967). Fiber sizes and capillary to fiber ratios in skeletal muscle of exercised rats. Anat Rec 159: 33–39CrossRefPubMedGoogle Scholar
  64. 64.
    Hudlicka O, Brown MD, Egginton S. (1992). Angiogenesis in skeletal and cardiac muscle. Physiol Rev 72: 369–417PubMedGoogle Scholar
  65. 65.
    Tesch PA, Thorson A, Kaiser P. (1984). Muscle capillary supply and fiber type characteristics in weight and power lifters. J. Appl Physiol 56: 35–38PubMedGoogle Scholar
  66. 66.
    Richardson RS, Grassi B, Gavin TP et al. (1999). Evidence of O2 supply-dependent VO2max in the exercise-trained human quadriceps. J Appl Physiol 86: 1048–53PubMedGoogle Scholar
  67. 67.
    Hepple RT, Hogan MC, Stan C et al. (2000). Structural basis of muscle O2 diffusing capacity: evidence from muscle function in situ. J Appl Physiol 88: 560–66PubMedGoogle Scholar
  68. 68.
    Yang HT, Ogilvie RW, Terjung RL. (1994). Peripheral adaptations in trained aged rats with femoral artery stenosis. Circ Res 74: 235–43PubMedGoogle Scholar
  69. 69.
    Robinson DM, Ogilvie RW, Tullson PC et al. (1994). Increased peak oxygen consumption of trained muscle requires increased electron flux capacity. J Appl Physiol 77: 1941–52PubMedGoogle Scholar
  70. 70.
    Efthimiadou A, Asimakopoulos B, Nikolettos N et al. (2004).The angiogenetic effect of intramuscular administration of VEGF on muscle. The influence of exercise on angiogenesis. In Vivo 18: 825–9PubMedGoogle Scholar
  71. 71.
    Gigante B, Tarsitano M, Cimini V et al. (2004). Placenta growth factor is not required for exercise-induced angiogenesis. Angiogenesis 7: 277–84CrossRefPubMedGoogle Scholar
  72. 72.
    Husain K. (2004). Physical conditioning modulates rat cardiac vascular endothelial growth factor gene expression in nitric oxide-deficient hypertension. Biochem Biophys Res Commun 320: 1169–74CrossRefPubMedGoogle Scholar
  73. 73.
    Bloor C, Leon A. (1970). Interaction of age and exercise on the heart and its blood supply. Lab Invest 22: 160–5PubMedGoogle Scholar
  74. 74.
    Tomanek R. (1970). Effects of age and exercise on the extent of the myocardial capillary bed. Anat Rec 167: 55–62CrossRefPubMedGoogle Scholar
  75. 75.
    McKirnan MD, White FC, Bloor CM. (1995). Exercise-induced stunning of collateral dependent myocardium. FASEB J 9: A49Google Scholar
  76. 76.
    Roth DM, White FC, Nichols ML et al. (1990). Effect of long-term exercise on regional myocardial function and coronary collateral development after gradual coronary artery occlusion in pigs. Circulation 82:1778–89PubMedGoogle Scholar
  77. 77.
    White FC, Carroll SM, Magnet A et al. (1992). Coronary collateral development in the swine after coronary artery occlusion. Circ Res 71: 1490–1500PubMedGoogle Scholar
  78. 78.
    White FC, Roth DM, Bloor CM. (1989). Coronary collateral reserve during exercise-induced ischemia in swine. Basic Res Cardiol 84: 42–54CrossRefPubMedGoogle Scholar
  79. 79.
    Hastings AB, White FC, Sanders TM et al. (1982). Comparative physiological responses to exercise stress. J Appl Physiol 52: 1077–83PubMedGoogle Scholar
  80. 80.
    Clark EF, Clark EL. (1940). Microscopic observations in the extra endothelial cells of living mammalian blood vessels. Am J Anat 66: 1–49CrossRefGoogle Scholar
  81. 81.
    Tomanek RJ. (1994). Exercise-induced coronary angiogenesis: a review. Med Sci Sports Exer 26: 1245–51Google Scholar
  82. 82.
    White FC, McKirnan MD, Breisch EA et al. (1987). Adaptation of the left ventricle of exercise-induced hypertrophy. J Appl Physiol 62: 1097–1103CrossRefPubMedGoogle Scholar
  83. 83.
    Breisch EA, White FC, Nimmo LE et al. (1986). Exercise induced cardiac hypertrophy: a correlation of blood flow and microvasculature. J App Physiol 60: 1259–67Google Scholar
  84. 84.
    Gute D, Fraga C, Laughlin MH et al. (1996). Regional changes in capillary supply in skeletal muscle of high-intensity endurance-trained rats. J Appl Physiol 81: 619–26PubMedGoogle Scholar
  85. 85.
    Tang K, Breen EC, Gerber HP et al. (2004). Capillary regression in vascular endothelial growth factor-deficient skeletal muscle. Physiol Genomics 18: 63–9CrossRefGoogle Scholar
  86. 86.
    Hudlicka O, Brown M, Egginton S. (1992). Angiogenesis in skeletal and cardiac muscle. Physiol Rev 72: 369–417PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Colin M. Bloor
    • 1
  1. 1.Department of PathologyUniversity of CaliforniaSan DiegoUSA

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