Responses of Angiogenic Growth Factors to Exercise, to Hypoxia and to Exercise under Hypoxic Conditions

Abstract

The purpose of the present study was to compare the acute hormonal response of angiogenic regulators to a short-term hypoxic exposure at different altitudes with and without exercise. 7 subjects participated in 5 experimental trials. 2 times subjects stayed in a sedentary position for 90 min at 2 000 m or 4 000 m, respectively. The same was carried out again in combination with exercise at the same relative intensity (2 mmol∙L^− 1 of lactate). The fifth trial consisted of 90 min exercise at sea level. Venous blood samples were taken under resting conditions, 0 and 180 min after each condition to determine VEGF, EPO, IL-6, IL-8 and IGF-1 serum concentrations. EPO, VEGF, and IL-8 showed increases only, when hypoxia was combined with exercise. IL-6 was increased after exercise, independent of altitude. IGF-1 showed no changes in any intervention. The present study suggests that short term hypoxic exposure combined with low intensity exercise is able to up-regulate angiogenic regulators, which might be beneficial to induce angiogenesis and to improve endurance performance. However, in some cases high altitudes are needed, or it can be speculated that exercise intensity needs to be increased.

Key words

angiogenesis - VEGF - EPO - IL-6 - IL-8 - IGF-1

• References

• 1 Akerstrom T, Steensberg A, Keller P, Keller C, Penkowa M, Pedersen BK. Exercise induces interleukin-8 expression in human skeletal muscle. J Physiol 2005; 563: 507-516
• 2 Alemany JA, Nindl BC, Kellogg MD, Tharion WJ, Young AJ, Montain SJ. Effects of dietary protein content on IGF-I, testosterone, and body composition during 8 days of severe energy deficit and arduous physical activity. J Appl Physiol 2008; 105: 58-64
• 3 Brown MD, Hudlicka O. Modulation of physiological angiogenesis in skeletal muscle by mechanical forces: involvement of VEGF and metalloproteinases. Angiogenesis 2003; 6: 1-14
• 4 Chan MH, Carey AL, Watt MJ, Febbraio MA. Cytokine gene expression in human skeletal muscle during concentric contraction: evidence that IL-8, like IL-6, is influenced by glycogen availability. Am J Physiol 2004; 287: R322-R327
• 5 Cohen T, Nahari D, Cerem LW, Neufeld G, Levi BZ. Interleukin 6 induces the expression of vascular endothelial growth factor. J Biol Chem 1996; 271: 736-741
• 6 De Palo EF, Antonelli G, Gatti R, Chiappin S, Spinella P, Cappellin E. Effects of two different types of exercise on GH/IGF axis in athletes. Is the free/total IGF-I ratio a new investigative approach?. Clin Chim Acta 2008; 387: 71-74
• 7 Eckardt KU, Boutellier U, Kurtz A, Schopen M, Koller EA, Bauer C. Rate of erythropoietin formation in humans in response to acute hypobaric hypoxia. J Appl Physiol 1989; 66: 1785-1788
• 8 Egginton S. Invited review: activity-induced angiogenesis. Pflugers Arch 2009; 457: 963-977
• 9 Egginton S, Hudlicka O, Brown MD, Walter H, Weiss JB, Bate A. Capillary growth in relation to blood flow and performance in overloaded rat skeletal muscle. J Appl Physiol 1998; 85: 2025-2032
• 10 Fandrey J. Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression. Am J Physiol 2004; 286: R977-R988
• 11 Ferrara N. Vascular endothelial growth factor. Arterioscler Thromb Vasc Biol 2009; 29: 789-791
• 12 Forsythe JA, Jiang BH, 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 1996; 16: 4604-4613
• 13 Frystyk J. Exercise and the growth hormone-insulin-like growth factor axis. Med Sci Sports Exerc 2010; 42: 58-66
• 14 Harriss DJ, Atkinson G. Update – ethical standards in sport and exercise science research. Int J Sports Med 2011; 32: 819-821
• 15 Hartmann G, Tschop M, Fischer R, Bidlingmaier C, Riepl R, Tschop K, Hautmann H, Endres S, Toepfer M. High altitude increases circulating interleukin-6, interleukin-1 receptor antagonist and C-reactive protein. Cytokine 2000; 12: 246-252
• 16 Helge JW, Stallknecht B, Pedersen BK, Galbo H, Kiens B, Richter EA. The effect of graded exercise on IL-6 release and glucose uptake in human skeletal muscle. J Physiol 2003; 546: 299-305
• 17 Karakurum M, Shreeniwas R, Chen J, Pinsky D, Yan SD, Anderson M, Sunouchi K, Major J, Hamilton T, Kuwabara K. Hypoxic induction of interleukin-8 gene expression in human endothelial cells. J Clin Invest 1994; 93: 1564-1570
• 18 Keller C, Steensberg A, Pilegaard H, Osada T, Saltin B, Pedersen BK, Neufer PD. Transcriptional activation of the IL-6 gene in human contracting skeletal muscle: influence of muscle glycogen content. FASEB J 2001; 15: 2748-2750
• 19 Klausen T, Olsen NV, Poulsen TD, Richalet JP, Pedersen BK. Hypoxemia increases serum interleukin-6 in humans. Eur J Appl Physiol 1997; 76: 480-482
• 20 Koistinen H, Koistinen R, Selenius L, Ylikorkala Q, Seppala M. Effect of marathon run on serum IGF-I and IGF-binding protein 1 and 3 levels. J Appl Physiol 1996; 80: 760-764
• 21 Lundby C, Steensberg A. Interleukin-6 response to exercise during acute and chronic hypoxia. Eur J Appl Physiol 2004; 91: 88-93
• 22 Mazzeo RS, Donovan D, Fleshner M, Butterfield GE, Zamudio S, Wolfel EE, Moore LG. Interleukin-6 response to exercise and high-altitude exposure: influence of alpha-adrenergic blockade. J Appl Physiol 2001; 91: 2143-2149
• 23 Mucci P, Durand F, Lebel B, Bousquet J, Prefaut C. Interleukins 1-beta,  − 8, and histamine increases in highly trained, exercising athletes. Med Sci Sports Exerc 2000; 32: 1094-1100
• 24 Ostrowski K, Schjerling P, Pedersen BK. Physical activity and plasma interleukin-6 in humans – effect of intensity of exercise. Eur J Appl Physiol 2000; 83: 512-515
• 25 Pedersen BK, Steensberg A, Schjerling P. Muscle-derived interleukin-6: possible biological effects. J Physiol 2001; 536: 329-337
• 26 Prior BM, Yang HT, Terjung RL. What makes vessels grow with exercise training?. J Appl Physiol 2004; 97: 1119-1128
• 27 Richalet JP, Letournel M, Souberbielle JC. Effects of high-altitude hypoxia on the hormonal response to hypothalamic factors. Am J Physiol 2010; 299: R1685-R1692
• 28 Sasaki H, Ray PS, Zhu L, Galang N, Maulik N. Oxidative stress due to hypoxia/reoxygenation induces angiogenic factor VEGF in adult rat myocardium: possible role of NFkappaB. Toxicology 2000; 155: 27-35
• 29 Schmidt W, Dore S, Hilgendorf A, Strauch S, Gareau R, Brisson GR. Effects of exercise during normoxia and hypoxia on the growth hormone-insulin-like growth factor I axis. Eur J Appl Physiol 1995; 71: 424-430
• 30 Schmidt W, Eckardt KU, Hilgendorf A, Strauch S, Bauer C. Effects of maximal and submaximal exercise under normoxic and hypoxic conditions on serum erythropoietin level. Int J Sports Med 1991; 12: 457-461
• 31 Schwarz AJ, Brasel JA, Hintz RL, Mohan S, Cooper DM. Acute effect of brief low- and high-intensity exercise on circulating insulin-like growth factor (IGF) I, II, and IGF-binding protein-3 and its proteolysis in young healthy men. J Clin Endocrinol Metab 1996; 81: 3492-3497
• 32 Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 1992; 359: 843-845
• 33 Simonini A, Moscucci M, Muller DW, Bates ER, Pagani FD, Burdick MD, Strieter RM. IL-8 is an angiogenic factor in human coronary atherectomy tissue. Circulation 2000; 101: 1519-1526
• 34 Steensberg A, van Hall G, Osada T, Sacchetti M, Saltin B, Klarlund PB. Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. J Physiol 2000; 529 (Pt 1) 237-242
• 35 Stefanini MO, Wu FT, Mac GF, Popel AS. A compartment model of VEGF distribution in blood, healthy and diseased tissues. BMC Syst Biol 2008; 2: 77-
• 36 Stokes K, Nevill M, Frystyk J, Lakomy H, Hall G. Human growth hormone responses to repeated bouts of sprint exercise with different recovery periods between bouts. J Appl Physiol 2005; 99: 1254-1261
• 37 Suhr F, Brixius K, de Marees M, Bolck B, Kleinoder H, Achtzehn S, Bloch W, Mester J. Effects of short-term vibration and hypoxia during high-intensity cycling exercise on circulating levels of angiogenic regulators in humans. J Appl Physiol 2007; 103: 474-483
• 38 Sutton JR. Effect of acute hypoxia on the hormonal response to exercise. J Appl Physiol 1977; 42: 587-592
• 39 Wahl P, Zinner C, Achtzehn S, Bloch W, Mester J. Effect of high- and low-intensity exercise and metabolic acidosis on levels of GH, IGF-I, IGFBP-3 and cortisol. Growth Horm IGF Res 2010; 20: 380-385
• 40 Yan SF, Tritto I, Pinsky D, Liao H, Huang J, Fuller G, Brett J, May L, Stern D. Induction of interleukin 6 (IL-6) by hypoxia in vascular cells. Central role of the binding site for nuclear factor-IL-6. J Biol Chem 1995; 270: 11463-11471
• 41 Zwezdaryk KJ, Coffelt SB, Figueroa YG, Liu J, Phinney DG, LaMarca HL, Florez L, Morris CB, Hoyle GW, Scandurro AB. Erythropoietin, a hypoxia-regulated factor, elicits a pro-angiogenic program in human mesenchymal stem cells. Exp Hematol 2007; 35: 640-652