Exercise training improves age-related changes in cerebral capillary vascularity through the upregulation of PI3K / Akt signaling

Authors

  • Channipa Chanpakdee Chulalongkorn University, Bangkok, Thailand
  • Sheepsumon Viboolvorakul Faculty of Science, Rangsit University, Pathum-Thani, Thailand
  • Suthiluk Patumraj Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

Keywords:

Aging, exercise training, CD31, Akt

Abstract

Background: Currently, the number of the elderly has been rising sharply worldwide. Seemingly, age-induced cerebral endothelial dysfunction may lead to vascular abnormality that can later progress to cerebrovascular and neurodegenerative diseases. Moreover, several evidences have shown that age-related oxidative stress and decline in cellular function appeared in the vascular system both in humans and laboratory animals. The role of exercise training in the regulation of age-related oxidative stress and endothelial functions have been reported.

Objectives: To investigate whether exercise training can prevent age-induced cerebral endothelial dysfunction associated to PI3K/Akt signaling.

Methods: Male Wistar rats were randomly divided into 3 groups: sedentary-young group (SE-Young, 4 months), sedentary-aged group (SE-Aged, 22 - 24 months), and swimming trained-aged group (ET-Aged, 22 - 24 months), which individually swam 1 hour/day, 5 days/week for 8 weeks. After 8 weeks of the exercise period, the rats took rest for 24 hours. After a phosphate buffer saline (PBS) perfusion, brain was used for determining CD31 by immunohistochemistry. Vascular endothelial growth factor (VEGF), phospho-Akt level (p-Akt), and malondialdehyde (MDA) levels in the brain were measured by enzyme-linked immunosorbent assay.

Results: The aged rats’ physiological characteristics had significant alteration when compared to the young group (P < 0.05). However, ET-Aged rats showed significantly reduced resting mean arterial blood pressure when compared to the young group (P < 0.05). This study also showed that exercise could upregulate VEGF, p-Akt level, and increase CD31 in the ET-aged group. Furthermore, tissue MDA in ET-Aged rats was significantly reduced when compared to SE-Aged rats (P < 0.05).

Conclusion: Our findings imply that exercise training protected age-induced cerebral endothelial dysfunction associated with its effects of oxidative stress and PI3K/Akt signaling.

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References

Akinyemi RO, Mukaetova-Ladinska EB, Attems J, Ihara M, Kalaria RN. Vascular risk factors and neurodegeneration in ageing related dementias: Alzheimer's disease and vascular dementia. Curr Alzheimer Res 2013;10:642-53. https://doi.org/10.2174/15672050113109990037

Brown WR, Thore CR. Review: cerebral microvascular pathology in ageing and neurodegeneration. Neuropathol Appl Neurobiol 2011;37:56-74. https://doi.org/10.1111/j.1365-2990.2010.01139.x

Gupta A, Bhatnagar S. Vasoregression: A shared vascular pathology underlying macrovascular and microvascular pathologies? OMICS 2015;19:733-53. https://doi.org/10.1089/omi.2015.0128

Ding YH, Li J, Zhou Y, Rafols JA, Clark JC, Ding Y.Cerebral angiogenesis and expression of angiogenic factors in aging rats after exercise. Curr Neurovasc Res 2006;3:15-23.

https://doi.org/10.2174/156720206775541787

Davies PF, Spaan JA, Krams R. Shear stress biology of the endothelium. Ann Biomed Eng 2005;33:1714-8. https://doi.org/10.1007/s10439-005-8774-0

Resnick N, Yahav H, Shay-Salit A, Shushy M, Schubert S, Zilberman LC, et al. Fluid shear stress and the vascular endothelium: for better and for worse. Prog Biophys Mol Biol 2003;81:177-99.

https://doi.org/10.1016/S0079-6107(02)00052-4

Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci 2007;30:464-72. https://doi.org/10.1016/j.tins.2007.06.011

Iemitsu M, Maeda S, Jesmin S, Otsuki T, Miyauchi T. Exercise training improves aging-induced downregulation of VEGF angiogenic signaling cascade in hearts. Am J Physiol Heart Circ Physiol 2006;291:H1290-8. https://doi.org/10.1152/ajpheart.00820.2005

Viboolvorakul S, Patumraj S. Exercise training could improve age-related changes in cerebral blood flow and capillary vascularity through the upregulation of VEGF and eNOS. Biomed Res Int 2014;2014:230791. https://doi.org/10.1155/2014/230791

Wang X, Liu J, Zhu H, Tejima E, Tsuji K, Murata Y, et al. Effects of neuroglobin overexpression on acute brain injury and long-term outcomes after focal cerebral ischemia. Stroke 2008;39:1869-74.

https://doi.org/10.1161/STROKEAHA.107.506022

Wang D, Stockard CR, Harkins L, Lott P, Salih C, Yuan K. et al. Immunohistochemistry in the evaluation of neovascularization in tumor xenografts. Biotech Histochem 2008;83:179-89.

https://doi.org/10.1080/10520290802451085

Li W, Suwanwela NC, Patumraj S. Curcumin by down-regulating NF-kB and elevating Nrf2, reduces brain edema and neurological dysfunction after cerebral I/R. Microvasc Res 2016;106:117-27.

https://doi.org/10.1016/j.mvr.2015.12.008

LeBlanc AJ, Shipley RD, Kang LS, Muller-Delp JM. Age impairs Flk-1 signaling and NO-mediated vasodilation in coronary arterioles. Am J Physiol Heart Circ Physiol 2008;295:H2280-8.

https://doi.org/10.1152/ajpheart.00541.2008

Elmadfa I, Meyer AL. Body composition, changing physiological functions and nutrient requirements of the elderly. Ann Nutr Metab 2008;52 Suppl 1:2-5. https://doi.org/10.1159/000115339

Gallagher D, Ruts E, Visser M, Heshka S, Baumgartner RN, Wang J, et al. Weight stability masks sarcopenia in elderly men and women. Am J Physiol Endocrinol Metab 2000;279:E366-75.

https://doi.org/10.1152/ajpendo.2000.279.2.E366

LaMonte MJ, Blair SN. Physical activity, cardiorespiratory fitness, and adiposity: contributions to disease risk. Curr Opin Clin Nutr Metab Care 2006;9:540-6.

https://doi.org/10.1097/01.mco.0000241662.92642.08

Duvigneaud N, Matton L, Wijndaele K, Deriemaeker P, Lefevre J, Philippaerts R, et al. Relationship of obesity with physical activity, aerobic fitness and muscle strength in Flemish adults. J Sports Med Phys Fitness 2008;48:201-10.

Stenholm S, Harris TB, Rantanen T, Visser M, Kritchevsky SB, Ferrucci L. Sarcopenic obesity: definition, cause and consequences. Curr Opin Clin Nutr Metab Care 2008;11:693-700.

https://doi.org/10.1097/MCO.0b013e328312c37d

Kusunoki M, Tsutsumi K, Hara T, Ogawa H, Nakamura T, Miyata T, et al. A lipoprotein lipase activator, NO-1886 prevents impaired endothelium-dependent relaxation of aorta caused by exercise in aged rats. Exp Gerontol 2002;37:891-6. https://doi.org/10.1016/S0531-5565(02)00023-2

Caponi PW, Lehnen AM, Pinto GH, Borges J, Markoski M, Machado UF, et al. Aerobic exercise training induces metabolic benefits in rats with metabolic syndrome independent of dietary changes. Clinics (Sao Paulo) 2013;68:1010-7. https://doi.org/10.6061/clinics/2013(07)20

Küng CF, Lüscher TF. Different mechanisms of endothelial dysfunction with aging and hypertension in rat aorta. Hypertension 1995;25:194-200. https://doi.org/10.1161/01.HYP.25.2.194

Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a "set up" for vascular disease. Circulation 2003;107:139-46.

https://doi.org/10.1161/01.CIR.0000048892.83521.58

Vanhoutte PM, Shimokawa H, Tang EH, Feletou M. Endothelial dysfunction and vascular disease. Acta Physiol (Oxf) 2009;196:193-222. https://doi.org/10.1111/j.1748-1716.2009.01964.x

Ross R. The pathogenesis of atherosclerosis-an update. N Engl J Med 1986;314:488-500.

https://doi.org/10.1056/NEJM198602203140806

Panza JA, Quyyumi AA, Brush JE Jr, Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 1990;323: 22-7.

https://doi.org/10.1056/NEJM199007053230105

Panza JA, Casino PR, Badar DM, Quyyumi AA. Effect of increased availability of endothelium-derived nitric oxide precursor on endothelium-dependent vascular relaxation in normal subjects and in patients with essential hypertension. Circulation 1993;87:1475-81.

https://doi.org/10.1161/01.CIR.87.5.1475

Spirduso W, Francis KL, MacRae PG. Physical dimensions of aging. 2nd ed. Champaign: Human Kinetics. 2005.

O'Rourke MF, Hashimoto J. Mechanical factors in arterial aging: a clinical perspective. J Am Coll Cardiol 2007;50:1-13. https://doi.org/10.1016/j.jacc.2006.12.050

Zalba G, Beaumont FJ, San José G, Fortuño A, Fortuño MA, Etayo JC, et al. Vascular NADH/NADPH oxidase is involved in enhanced superoxide production in spontaneously hypertensive rats. Hypertension 2000;35:1055-61. https://doi.org/10.1161/01.HYP.35.5.1055

Liu H, Yang Y, Huang G, Tan S, Liu Y. Positive association of pro-inflammatory biomarkers and increased oxidative stress in the healthy elderly. Arch Gerontol Geriatr 2012;54:e8-e12.

https://doi.org/10.1016/j.archger.2011.05.016

Rush JW, Turk JR, Laughlin MH. Exercise training regulates SOD-1 and oxidative stress in porcine aortic endothelium. Am J Physiol Heart Circ Physiol 2003;284:H1378-87.

https://doi.org/10.1152/ajpheart.00190.2002

Yamashita N, Hoshida S, Otsu K, Asahi M, Kuzuya T, Hori M. Exercise provides direct biphasic cardioprotection via manganese superoxide dismutase activation. J Exp Med 1999;189:1699-706.

https://doi.org/10.1084/jem.189.11.1699

Yung LM, Laher I, Yao X, Chen ZY, Huang Y, Leung FP. Exercise, vascular wall and cardiovascular diseases: an update (part 2). Sports Med 2009;39:45-63. https://doi.org/10.2165/00007256-200939010-00004

Jiang T, Yin F, Yao J, Brinton RD, Cadenas E. Lipoic acid restores age-associated impairment of brain energy metabolism through the modulation of Akt/ JNK signaling and PGC1alpha transcriptional pathway. Aging Cell 2013;12:1021-31. https://doi.org/10.1111/acel.12127

Li M, Li C, Parkhouse WS. Age-related differences in the des IGF-I-mediated activation of Akt-1 and p70 S6K in mouse skeletal muscle. Mech Ageing Dev 2003;124:771-8. https://doi.org/10.1016/S0047-6374(03)00124-6

Shay KP, Hagen TM. Age-associated impairment of Akt phosphorylation in primary rat hepatocytes is remediated by alpha-lipoic acid through PI3 kinase, PTEN, and PP2A. Biogerontology 2009;10:443-56.

https://doi.org/10.1007/s10522-008-9187-x

Centurione L, Antonucci A, Miscia S, Grilli A, Rapino M, Grifone G, et al. Age-related death-survival balance in myocardium: an immunohistochemical and biochemical study. Mech Ageing Dev 2002;123:341-50. https://doi.org/10.1016/S0047-6374(01)00378-5

Verschoor CP, Johnstone J, Loeb M, Bramson JL, Bowdish DM. Anti-pneumococcal deficits of monocyte-derived macrophages from the advancedage, frail elderly and related impairments in PI3K-AKT signaling. Hum Immunol 2014;75:1192-6. https://doi.org/10.1016/j.humimm.2014.10.004

Takahashi H, Okamura D, Starr ME, Saito H, Evers BM. Age-dependent reduction of the PI3K regulatory subunit p85alpha suppresses pancreatic acinar cell proliferation. Aging Cell 2012;11:305-14.

https://doi.org/10.1111/j.1474-9726.2011.00787.x

Tomobe K, Shinozuka T, Kuroiwa M, Nomura Y. Agerelated changes of Nrf2 and phosphorylated GSK-3beta in a mouse model of accelerated aging (SAMP8). Arch Gerontol Geriatr 2012;54:e1-7.

https://doi.org/10.1016/j.archger.2011.06.006

Pusztaszeri MP, Seelentag W, Bosman FT. Immunohistochemical expression of endothelial markers CD31, CD34, von Willebrand factor, and Fli-1 in normal human tissues. J Histochem Cytochem 2006;54:385-95. https://doi.org/10.1369/jhc.4A6514.2005

Gill R, O'Donnell RJ, Horvai A. Utility of immunohistochemistry for endothelial markers in distinguishing epithelioid hemangioendothelioma from carcinoma metastatic to bone. Arch Pathol Lab Med 2009;133:967-72. https://doi.org/10.5858/133.6.967

Donato AJ, Eskurza I, Silver AE, Levy AS, Pierce GL, Gates PE, et al. Direct evidence of endothelial oxidative stress with aging in humans: relation to impaired endothelium-dependent dilation and upregulation of nuclear factor-kappaB. Circ Res 2007;100:1659-66.

https://doi.org/10.1161/01.RES.0000269183.13937.e8

Jablonski KL, Seals DR, Eskurza I, Monahan KD, Donato AJ. High-dose ascorbic acid infusion abolishes chronic vasoconstriction and restores resting leg blood flow in healthy older men. J Appl Physiol (1985) 2007;103:1715-21. https://doi.org/10.1152/japplphysiol.00533.2007

Csiszar A, Ungvari Z, Edwards JG, Kaminski P, Wolin MS, Koller A, et al. Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function. Circ Res 2002;90:1159-66.

https://doi.org/10.1161/01.RES.0000020401.61826.EA

Ziche M, Morbidelli L, Choudhuri R, Zhang HT, Donnini S, Granger HJ, et al. Nitric oxide synthase lies downstream from vascular endothelial growth factor-induced but not basic fibroblast growth factorinduced angiogenesis. J Clin Invest 1997;99:2625-34. https://doi.org/10.1172/JCI119451

Li JY, Zhang Y, Zhang WH, Jia S, Kang Y, Tian R. Effects of differential distribution of microvessel density, possibly regulated by miR-374a, on breast cancer prognosis. Asian Pac J Cancer Prev 2013;14:1715-20. https://doi.org/10.7314/APJCP.2013.14.3.1715

Shibuya M, Claesson-Welsh L. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res 2006;312:549-60. https://doi.org/10.1016/j.yexcr.2005.11.012

Tomanek RJ. Effects of age and exercise on the extent of the myocardial capillary bed. Anat Rec 1970;167:55-62. https://doi.org/10.1002/ar.1091670106

Osawa M, Masuda M, Harada N, Lopes RB, Fujiwara K. Tyrosine phosphorylation of platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) in mechanically stimulated vascular endothelial cells. Eur J Cell Biol 1997;72:229-37.

McSweeney SR, Warabi E, Siow RC. Nrf2 as an Endothelial Mechanosensitive Transcription Factor: Going With the Flow. Hypertension 2016;67:20-9. https://doi.org/10.1161/HYPERTENSIONAHA.115.06146

Cho H, Thorvaldsen JL, Chu Q, Feng F, Birnbaum MJ. Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J Biol Chem 2001;276:38349-52.

https://doi.org/10.1074/jbc.C100462200

Muslin AJ, DeBosch B. Role of Akt in cardiac growth and metabolism. Novartis Found Symp 2006;274:118-26. https://doi.org/10.1002/0470029331.ch8

Wick W, Furnari FB, Naumann U, Cavenee WK, Weller M. PTEN gene transfer in human malignant glioma: sensitization to irradiation and CD95L-induced apoptosis. Oncogene 1999;18:3936-43.

https://doi.org/10.1038/sj.onc.1202774

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Published

2023-08-15

How to Cite

1.
Chanpakdee C, Viboolvorakul S, Patumraj S. Exercise training improves age-related changes in cerebral capillary vascularity through the upregulation of PI3K / Akt signaling. Chula Med J [Internet]. 2023 Aug. 15 [cited 2024 Oct. 12];63(4). Available from: https://he05.tci-thaijo.org/index.php/CMJ/article/view/304

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