Abstract
Exercise is beneficial to brain health, and historically, the advantageous effects of exercise on the brain have been attributed to neuronal plasticity. However, it has also become clear that the brain vascular system also exhibits plasticity in response to exercise. This plasticity occurs in areas involved in movement, such as the motor cortex. This experiment aimed to further characterize the effects of exercise on structural vascular plasticity in the male rat motor cortex, by specifically identifying whether features of angiogenesis, the growth of new capillaries, or changes in vessel diameter were present. Male rats in the exercise group engaged in a 5-week bout of voluntary wheel running, while a second group of rats remained sedentary. After the exercise regimen, vascular corrosion casts, resin replicas of the brain vasculature, were made for all animals and imaged using a scanning electron microscope. Results indicate sprouting angiogenesis was the primary form of structural vascular plasticity detected in the motor cortex under these aerobic exercise parameters. Additionally, exercised rats displayed a slight increase in capillary diameter and expanded endothelial cell nuclei diameters in this region.
Similar content being viewed by others
References
Ackermann M, Konerding MA (2015) Vascular casting for the study of vascular morphogenesis. In: Ribatti D (ed) Vascular morphogenesis: methods and protocolsm. Springer, New York, pp 49–66
Adair TH, Montani J-P (2010) Overview of angiogenesis, Morgan & Claypool Life Sciences.
Arribas SM, González C, Graham D, Dominiczak AF, McGrath JC (1997) Cellular changes induced by chronic nitric oxide inhibition in intact rat basilar arteries revealed by confocal microscopy. J Hypertens 15:1685
Babiak A et al (2004) Coordinated activation of VEGFR-1 and VEGFR-2 is a potent arteriogenic stimulus leading to enhancement of regional perfusion. Cardiovasc Res 61:789–795
Barnes JN, Corkery AT (2020) Exercise improves vascular function, but does this translate to the brain? Brain Plast 4:65–79
Black JE, Isaacs KR, Anderson BJ, Alcantara AA, Greenough WT (1990) Learning causes synaptogenesis, whereas motor activity causes angiogenesis, in cerebellar cortex of adult rats. Proc Natl Acad Sci USA 87:5568–5572
Bloor CM (2005) Angiogenesis during exercise and training. Angiogenesis 8:263–271
Brockett AT, LaMarca EA, Gould E (2015) Physical exercise enhances cognitive flexibility as well as astrocytic and synaptic markers in the medial prefrontal cortex. PLoS ONE 10:e0124859
Brown J et al (2003) Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis. Eur J Neurosci 17:2042–2046
Burri PH, Hlushchuk R, Djonov V (2004) Intussusceptive angiogenesis: its emergence, its characteristics, and its significance. Dev Dyn 231:474–488
Buschmann I, Schaper W (1999) Arteriogenesis versus angiogenesis: two mechanisms of vessel growth. Physiology 14:121–125
Carmeliet P (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med 6:389–395
Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473:298–307
Chantler PD et al (2015) Cerebral cortical microvascular rarefication in metabolic syndrome is dependent on insulin resistance and loss of nitric oxide bioavailability. Microcirculation 22:435–445
Chinsomboon J et al (2009) The transcriptional coactivator PGC-1alpha mediates exercise-induced angiogenesis in skeletal muscle. Proc Natl Acad Sci USA 106:21401–21406
Christensen LOD et al (2000) Cerebral activation during bicycle movements in man. Exp Brain Res 135:66–72
Christoffersonm RH, Nilsson BO (1988) Microvascular corrosion casting with analysis in the scanning electron microscope. Scanning 10:43–63
Clark PJ et al (2008) Intact neurogenesis is required for benefits of exercise on spatial memory but not motor performance or contextual fear conditioning in C57BL/6J mice. Neuroscience 155:1048–1058
Clark PJ, Brzezinska WJ, Puchalski EK, Krone DA, Rhodes JS (2009) Functional analysis of neurovascular adaptations to exercise in the dentate gyrus of young adult mice associated with cognitive gain. Hippocampus 19:937–950
Conway EM, Collen D, Carmeliet P (2001) Molecular mechanisms of blood vessel growth. Cardiovasc Res 49:507–521
Cotman CW, Berchtold NC (2002) Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci 25:295–301
Csiszar A et al (2017) Hypertension impairs neurovascular coupling and promotes microvascular injury: role in exacerbation of Alzheimer’s disease. GeroScience 39:359–372
Cudmore RH, Dougherty SE, Linden DJ (2017) Cerebral vascular structure in the motor cortex of adult mice is stable and is not altered by voluntary exercise. J Cereb Blood Flow Metab 37:3725–3743
De Silva TM, Faraci FM (2016) Microvascular dysfunction and cognitive impairment. Cell Mol Neurobiol 36:241–258
Deak F, Freeman WM, Ungvari Z, Csiszar A, Sonntag WE (2016) Recent developments in understanding brain aging: implications for Alzheimer’s disease and vascular cognitive impairment. J Gerontol Ser A 71:13–20
Deng J, Zhang J, Feng C, Xiong L, Zuo Z (2014) Critical role of matrix metalloprotease-9 in chronic high fat diet-induced cerebral vascular remodelling and increase of ischaemic brain injury in mice. Cardiovasc Res 103:473–484
Di Francescomarino S, Sciartilli A, Di Valerio V, Di Baldassarre A, Gallina S (2009) The effect of physical exercise on endothelial function. Sports Med 39:797–812
Ding Y et al (2004a) Exercise pre-conditioning reduces brain damage in ischemic rats that may be associated with regional angiogenesis and cellular overexpression of neurotrophin. Neuroscience 124:583–591
Ding Y-H et al (2004b) Exercise-induced overexpression of angiogenic factors and reduction of ischemia / reperfusion injury in stroke. Curr Neurovasc Res 5:411–420
Ding Y-H, Ding Y, Li J, Bessert DA, Rafols JA (2006a) Exercise pre-conditioning strengthens brain microvascular integrity in a rat stroke model. Neurol Res 28:184–189
Ding Y-H et al (2006b) Cerebral angiogenesis and expression of angiogenic factors in aging rats after exercise. Curr Neurovasc Res 3:15–23
Djonov V, Baum O, Burri PH (2003) Vascular remodeling by intussusceptive angiogenesis. Cell Tissue Res 314:107–117
Dorr A et al (2017) Effects of voluntary exercise on structure and function of cortical microvasculature. J Cereb Blood Flow Metab 37:1046–1059
Erickson MA, Banks WA (2013) Blood–brain barrier dysfunction as a cause and consequence of Alzheimer’s disease. J Cereb Blood Flow Metab 33:1500–1513
Fabel K, Kempermann G (2008) Physical activity and the regulation of neurogenesis in the adult and aging brain. Neuromolecular Med 10:59–66
Farmer J et al (2004) Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo. Neuroscience 124:71–79
Filipa M et al (2013) Endothelial cell–dependent regulation of arteriogenesis. Circ Res 113:1076–1086
Fontes EB et al (2015) Brain activity and perceived exertion during cycling exercise: an fMRI study. Br J Sports Med 49:556–560
Halliday MR, Abeydeera D, Lundquist AJ, Petzinger GM, Jakowec MW (2019) Intensive treadmill exercise increases expression of hypoxia-inducible factor 1α and its downstream transcript targets: a potential role in neuroplasticity. NeuroReport 30:619–627
Hase Y et al (2019) White matter capillaries in vascular and neurodegenerative dementias. Acta Neuropathol Commun 7:16
Heil M, Eitenmüller I, Schmitz-Rixen T, Schaper W (2006) Arteriogenesis versus angiogenesis: similarities and differences. J Cell Mol Med 10:45–55
Hillman CH, Erickson KI, Kramer AF (2008) Be smart, exercise your heart: exercise effects on brain and cognition. Nat Rev Neurosci 9:58–65
Hoier B et al (2012) Pro- and anti-angiogenic factors in human skeletal muscle in response to acute exercise and training. J Physiol 590:595–606
Hübner L, Godde B, Voelcker-Rehage C (2018) Acute exercise as an intervention to trigger motor performance and EEG beta activity in older adults. Neural Plast 2018:4756785
Hudlicka O, Brown MD, May S, Zakrzewicz A, Pries AR (2006) Changes in capillary shear stress in skeletal muscles exposed to long-term activity: role of nitric oxide. Microcirculation 13:249–259
Iadecola C, Davisson RL (2008) Hypertension and cerebrovascular dysfunction. Cell Metab 7:476–484
Isaacs KR, Anderson BJ, Alcantara AA, Black JE, Greenough WT (1992) Exercise and the brain: angiogenesis in the adult rat cerebellum after vigorous physical activity and motor skill learning. J Cereb Blood Flow Metab 12:110–119
Jin K et al (2002) Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci USA 99:11946–11950
Junichiro S et al (2003) Cerebral vascular abnormalities in a murine model of hereditary hemorrhagic telangiectasia. Stroke 34:783–789
Kerr AL, Swain RA (2011) Rapid cellular genesis and apoptosis: effects of exercise in the adult rat. Behav Neurosci 125:1–9
Kerr AL, Steuer EL, Pochtarev V, Swain RA (2010) Angiogenesis but not neurogenesis is critical for normal learning and memory acquisition. Neuroscience 171:214–226
Kinni H et al (2011) Cerebral metabolism after forced or voluntary physical exercise. Brain Res 1388:48–55
Kiuchi T, Lee H, Mikami T (2012) Regular exercise cures depression-like behavior via VEGF-Flk-1 signaling in chronically stressed mice. Neuroscience 207:208–217
Kleim JA, Cooper NR, VandenBerg PM (2002) Exercise induces angiogenesis but does not alter movement representations within rat motor cortex. Brain Res 934:1–6
Kon K, Fujii S, Kosaka H, Fujiwara T (2003) Nitric oxide synthase inhibition by N(G)-nitro-l-arginine methyl ester retards vascular sprouting in angiogenesis. Microvasc Res 65:2–8
Krucker T, Lang A, Meyer EP (2006) New polyurethane-based material for vascular corrosion casting with improved physical and imaging characteristics. Microsc Res Tech 69:138–147
Kus LH et al (2014) Angiogenesis in costal cartilage graft laryngotracheoplasty: a corrosion casting study in piglets. The Laryngoscope 124:2411–2417
Lange-Asschenfeldt C, Kojda G (2008) Alzheimer’s disease, cerebrovascular dysfunction and the benefits of exercise: From vessels to neurons. Exp Gerontol 43:499–504
Latimer CS et al (2011) Reversal of glial and neurovascular markers of unhealthy brain aging by exercise in middle-aged female mice. PLoS One 6:e26812
Lee J-W, Bae S-H, Jeong J-W, Kim S-H, Kim K-W (2004) Hypoxia-inducible factor (HIF-1)α: its protein stability and biological functions. Exp Mol Med 36:1–12
Leuner B, Gould E, Shors TJ (2002) Is there a link between adult neurogenesis and learning? Hippocampus 12:578–584
Li J et al (2005) Increased astrocyte proliferation in rats after running exercise. Neurosci Lett 386:160–164
Li S, Haigh K, Haigh JJ, Vasudevan A (2013) Endothelial VEGF sculpts cortical cytoarchitecture. J Neurosci 33:14809–14815
Lloyd PG, Prior BM, Yang HT, Terjung RL (2003) Angiogenic growth factor expression in rat skeletal muscle in response to exercise training. Am J Physiol Heart Circ Physiol 284:H1668–H1678
Lopez-Lopez C, LeRoith D, Torres-Aleman I (2004) Insulin-like growth factor I is required for vessel remodeling in the adult brain. Proc Natl Acad Sci 101:9833–9838
Makanya AN, Hlushchuk R, Djonov VG (2009) Intussusceptive angiogenesis and its role in vascular morphogenesis, patterning, and remodeling. Angiogenesis 12:113–123
Marín-Burgin A, Schinder AF (2012) Requirement of adult-born neurons for hippocampus-dependent learning. Behav Brain Res 227:391–399
Masamoto K et al (2014) Microvascular sprouting, extension, and creation of new capillary connections with adaptation of the neighboring astrocytes in adult mouse cortex under chronic hypoxia. J Cereb Blood Flow Metab 34:325–331
McCloskey DP, Adamo DS, Anderson BJ (2001) Exercise increases metabolic capacity in the motor cortex and striatum, but not in the hippocampus. Brain Res 891:168–175
Mentzer SJ, Konerding MA (2014) Intussusceptive angiogenesis: expansion and remodeling of microvascular networks. Angiogenesis 17:499–509
Meyer EP, Ulmann-Schuler A, Staufenbiel M, Krucker T (2008) Altered morphology and 3D architecture of brain vasculature in a mouse model for Alzheimer’s disease. Proc Natl Acad Sci USA 105:3587–3592
Morland C et al (2017) Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1. Nat Commun 8:15557
Nowak-Sliwinska P et al (2018) Consensus guidelines for the use and interpretation of angiogenesis assays. Angiogenesis 21:425–532
Olfert IM, Baum O, Hellsten Y, Egginton S (2016) Advances and challenges in skeletal muscle angiogenesis. Am J Physiol Heart Circ Physiol 310:H326–H336
Padilla J et al (2011) Vascular effects of exercise: endothelial adaptations beyond active muscle beds. Physiol Bethesda Md 26:132–145
Palmer TD, Willhoite AR, Gage FH (2000) Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 425:479–494
Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC (2006) HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 3:187–197
Paxinos G, Watson C (2013) The rat brain in stereotaxic coordinates, 7th edn. Cambridge Academic Press, Cambridge
Pereira AC et al (2007) An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci USA 104:5638–5643
Podcasy JL (2016) Considering sex and gender in Alzheimer disease and other dementias. Dialogues Clin Neurosci 18:437–446
Pugh CW, Ratcliffe PJ (2003) Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 9:677–684
Querido JS, Sheel AW (2007) Regulation of cerebral blood flow during exercise. Sports Med 37:765–782
Rhyu IJ et al (2010) Effects of aerobic exercise training on cognitive function and cortical vascularity in monkeys. Neuroscience 167:1239–1248
Ribatti D, Crivellato E (2012) “Sprouting angiogenesis”, a reappraisal. Dev Biol 372:157–165
Riddle DR, Sonntag WE, Lichtenwalner RJ (2003) Microvascular plasticity in aging. Ageing Res Rev 2:149–168
Rosa AI et al (2010) The angiogenic factor angiopoietin-1 is a proneurogenic peptide on subventricular zone stem/progenitor cells. J Neurosci 30:4573–4584
Schierling W et al (2009) Increased intravascular flow rate triggers cerebral arteriogenesis. J Cereb Blood Flow Metab 29:726–737
Schmidt W, Endres M, Dimeo F, Jungehulsing GJ (2013) Train the vessel, gain the brain: physical activity and vessel function and the impact on stroke prevention and outcome in cerebrovascular disease. Cerebrovasc Dis 35:303–312
Shimada H et al (2017) Effects of exercise on brain activity during walking in older adults: a randomized controlled trial. J NeuroEngineering Rehabil 14:50
Siddiqui AJ et al (2003) Combination of angiopoietin-1 and vascular endothelial growth factor gene therapy enhances arteriogenesis in the ischemic myocardium. Biochem Biophys Res Commun 310:1002–1009
Smeyne M, Sladen P, Jiao Y, Dragatsis I, Smeyne RJ (2015) HIF1α is necessary for exercise-induced neuroprotection while HIF2α is needed for dopaminergic neuron survival in the substantia nigra pars compacta. Neuroscience 295:23–38
Smith JC, Paulson ES, Cook DB, Verber MD, Tian Q (2010) Detecting changes in human cerebral blood flow after acute exercise using arterial spin labeling: Implications for fMRI. J Neurosci Methods 191:258–262
Spiegelaere WD et al (2012) Intussusceptive angiogenesis: a biologically relevant form of angiogenesis. J Vasc Res 49:390–404
Steinert JR, Chernova T, Forsythe ID (2010) Nitric oxide signaling in brain function, dysfunction, and dementia. The Neuroscientist 16:435–452
Stevenson ME, Behnke VK, Swain RA (2018) Exercise pattern and distance differentially affect hippocampal and cerebellar expression of FLK-1 and FLT-1 receptors in astrocytes and blood vessels. Behav Brain Res 337:8–16
Styp-Rekowska B, Hlushchuk R, Pries AR, Djonov V (2011) Intussusceptive angiogenesis: pillars against the blood flow. Acta Physiol 202:213–223
Swain RA et al (2003) Prolonged exercise induces angiogenesis and increases cerebral blood volume in primary motor cortex of the rat. Neuroscience 117:1037–1046
Swain RA et al (2012) On aerobic exercise and behavioral and neural plasticity. Brain Sci 2:709–744
Takimoto M, Hamada T (2014) Acute exercise increases brain region-specific expression of MCT1, MCT2, MCT4, GLUT1, and COX IV proteins. J Appl Physiol 116:1238–1250
Thomas AG, Dennis A, Bandettini PA, Johansen-Berg H (2012) The effects of aerobic activity on brain structure. Front Psychol 3:86
Tkachenko E et al (2013) The nucleus of endothelial cell as a sensor of blood flow direction. Biol Open 2:1007–1012
Tucsek Z et al (2014) Aging exacerbates obesity-induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice. J Gerontol Ser A 69:1339–1352
van Praag H (2008) Neurogenesis and exercise: past and future directions. NeuroMolecular Med 10:128–140
van Praag H (2009) Exercise and the brain: something to chew on. Trends Neurosci 32:283–290
van Praag H, Kempermann G, Gage FH (1999a) Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 2:266–270
van Praag H, Christie BR, Sejnowski TJ, Gage FH (1999b) Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci USA 96:13427–13431
van Praag H, Shubert T, Zhao C, Gage FH (2005) Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci 25:8680–8685
Van Steenkiste C et al (2010) Vascular corrosion casting: analyzing wall shear stress in the portal vein and vascular abnormalities in portal hypertensive and cirrhotic rodents. Lab Invest 90:1558–1572
Vivar C, Peterson BD, van Praag H (2016) Running rewires the neuronal network of adult-born dentate granule cells. NeuroImage 131:29–41
Voss MW, Nagamatsu LS, Liu-Ambrose T, Kramer AF (2011) Exercise, brain, and cognition across the life span. J Appl Physiol 111:1505–1513
Wagner PD (2001) Skeletal muscle angiogenesis A possible role for hypoxia. Adv Exp Med Biol 502:21–38
Yu Q, Tao H, Wang X, Li M (2015) Targeting brain microvascular endothelial cells: a therapeutic approach to neuroprotection against stroke. Neural Regen Res 10:1882–1891
Zhang P et al (2013) Early exercise improves cerebral blood flow through increased angiogenesis in experimental stroke rat model. J NeuroEngineering Rehabil 10:43
Zhao L, Mao Z, Woody SK, Brinton RD (2016) Sex differences in metabolic aging of the brain: Insights into female susceptibility to Alzheimer’s disease. Neurobiol Aging 42:69–79
Ziche M et al (1994) Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P. J Clin Invest 94:2036–2044
Acknowledgements
We would like to thank Amanda S. Nazario, Brittany S. Larsen, and Yael S. Greenburg for their contributions to data collection. When optimizing the vascular corrosion cast procedure, we appreciate the advice received from Dr. Eric P. Meyer and Dominic D. Quintana. We are also grateful to Dr. Marianna Orlova for her assistance with lyophilization of the samples.
Author information
Authors and Affiliations
Contributions
All authors contributed to the design of the experiment. The vascular corrosion casts were generated by MES and CCM. The scanning electron microscopy was completed by MES under the direction of HAO. Data were analyzed and interpreted by MES, and MES wrote the manuscript. All authors edited and approved the final manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Stevenson, M.E., Miller, C.C., Owen, H.A. et al. Aerobic exercise increases sprouting angiogenesis in the male rat motor cortex. Brain Struct Funct 225, 2301–2314 (2020). https://doi.org/10.1007/s00429-020-02100-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00429-020-02100-y