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Treadmill Exercise Promotes Neurogenesis in Ischemic Rat Brains via Caveolin-1/VEGF Signaling Pathways

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Abstract

Using a model of middle cerebral artery occlusion (MCAO), we have previously demonstrated that treadmill exercise promotes angiogenesis in the ischemic penumbra through caveolin-1/VEGF signaling pathways. However, the function of caveolin-1/VEGF signaling in neurogenesis after MCAO has not been determined. In this study, we aimed to investigate the potential of treadmill exercise to promote neurogenesis after MCAO and whether caveolin-1/VEGF signaling pathways are involved. After MCAO, rats were subjected to a program of treadmill exercise. Daidzein (a specific inhibitor of caveolin-1 protein expression, 0.4 mg/kg) was used to confirm the effect of caveolin-1/VEGF signaling on exercise-mediated neurogenesis. We found that the total protein expression of both caveolin-1 and VEGF was increased by exercise and consistent with the improved neurological recovery, decreased infarct volumes and increased 5-bromo-2′-deoxyuridine (BrdU) in the ipsilateral Subventricular zone (SVZ), as well as increased numbers of BrdU/DCX and BrdU/Neun-positive cells in the peri-infarct region. Furthermore, we observed that the treadmill exercise-induced increased VEGF expression, improved neurological recovery, decreased infarct volumes, increased BrdU/DCX and BrdU/Neun-positive cells were significantly inhibited by the caveolin-1 inhibitor. Our results indicate that treadmill exercise improves neurological recovery in ischemic rats, possibly by enhancement of SVZ-derived neural stem cell (NSC) proliferation, migration and differentiation in the penumbra. Moreover, caveolin-1/VEGF signaling is involved in exercise-mediated NSC migration and neuronal differentiation.

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Abbreviations

MCAO:

Middle cerebral artery occlusion

S:

Sham-operated

M:

Model

EM:

Exercise and model

IM:

Inhibitor and model

IEM:

Inhibitor, exercise, and model

SVZ:

Subventricular zone

SGZ:

The subgranular zone

NSC:

Neural stem cell

NPC:

Neural progenitor cell

VEGF:

Vascular endothelial growth factor

DCX:

Doublecortin

Neun:

Neuron-specific nuclear protein

BrdU:

5-Bromo-2′-deoxyuridine

EGF:

Epidermal growth factor

bFGF:

Basic fibroblast growth factor

BDNF:

Brain-derived neurotrophic factor

VEGFR2:

Vascular endothelial growth factor receptor 2

NMDAR:

N-Methyl-d-aspartate receptor

SFK:

Src family kinase

ERK:

Extracellular signal-regulated kinase

eNOS:

Endothelial nitric oxide synthase

GPCRs:

G protein coupled receptors

PLC:

Phosphoinositide-specific phospholipase C

Akt:

Protein kinase B

References

  1. Zeng X, Zhang G, Yang B, Zhang B, Zhang L, Ni Y, Liu C, Luo Y (2015) Neopterin as a predictor of functional outcome and mortality in chinese patients with acute ischemic stroke. Mol Neurobiol 53:3939–3947

    Article  PubMed  Google Scholar 

  2. Bellenchi GC, Volpicelli F, Piscopo V, Perrone-Capano C, di Porzio U (2013) Adult neural stem cells: an endogenous tool to repair brain injury? J Neurochem 124:159–167

    Article  CAS  PubMed  Google Scholar 

  3. Dai J, Li SQ, Qiu YM, Xiong WH, Yin YH, Jia F, Jiang JY (2013) Migration of neural stem cells to ischemic brain regions in ischemic stroke in rats. Neurosci Lett 552:124–128

    Article  CAS  PubMed  Google Scholar 

  4. Ohab JJ, Carmichael ST (2008) Poststroke neurogenesis: emerging principles of migration and localization of immature neurons. Neuroscientist 14:369–380

    Article  CAS  PubMed  Google Scholar 

  5. Yamashita T, Ninomiya M, Hernandez Acosta P, Garcia-Verdugo JM, Sunabori T, Sakaguchi M, Adachi K, Kojima T, Hirota Y, Kawase T, Araki N, Abe K, Okano H, Sawamoto K (2006) Subventricular zone-derived neuroblasts migrate and differentiate into mature neurons in the post-stroke adult striatum. J Neurosci 26:6627–6636

    Article  CAS  PubMed  Google Scholar 

  6. Kazanis I, Gorenkova N, Zhao JW, Franklin RJ, Modo M, Ffrench-Constant C (2013) The late response of rat subependymal zone stem and progenitor cells to stroke is restricted to directly affected areas of their niche. Exp Neurol 248:387–397

    Article  PubMed  PubMed Central  Google Scholar 

  7. Ohab JJ, Fleming S, Blesch A, Carmichael ST (2006) A neurovascular niche for neurogenesis after stroke. J Neurosci 26:13007–13016

    Article  CAS  PubMed  Google Scholar 

  8. Thored P, Wood J, Arvidsson A, Cammenga J, Kokaia Z, Lindvall O (2007) Long-term neuroblast migration along blood vessels in an area with transient angiogenesis and increased vascularization after stroke. Stroke 38:3032–3039

    Article  PubMed  Google Scholar 

  9. Hansen TM, Moss AJ, Brindle NP (2008) Vascular endothelial growth factor and angiopoietins in neurovascular regeneration and protection following stroke. Curr Neurovasc Res 5:236–245

    Article  CAS  PubMed  Google Scholar 

  10. Wang YQ, Guo X, Qiu MH, Feng XY, Sun FY (2007) VEGF overexpression enhances striatal neurogenesis in brain of adult rat after a transient middle cerebral artery occlusion. J Neurosci Res 85:73–82

    Article  CAS  PubMed  Google Scholar 

  11. Jasmin JF, Malhotra S, Singh Dhallu M, Mercier I, Rosenbaum DM, Lisanti MP (2007) Caveolin-1 deficiency increases cerebral ischemic injury. Circ Res 100:721–729

    Article  CAS  PubMed  Google Scholar 

  12. Head BP, Patel HH, Tsutsumi YM, Hu Y, Mejia T, Mora RC, Insel PA, Roth DM, Drummond JC, Patel PM (2008) Caveolin-1 expression is essential for N-methyl-d-aspartate receptor-mediated Src and extracellular signal-regulated kinase 1/2 activation and protection of primary neurons from ischemic cell death. FASEB J 22:828–840

    Article  CAS  PubMed  Google Scholar 

  13. Gao Y, Zhao Y, Pan J, Yang L, Huang T, Feng X, Li C, Liang S, Zhou D, Liu C, Tu F, Tao C, Chen X (2014) Treadmill exercise promotes angiogenesis in the ischemic penumbra of rat brains through caveolin-1/VEGF signaling pathways. Brain Res 1585:83–90

    Article  CAS  PubMed  Google Scholar 

  14. Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84–91

    Article  CAS  PubMed  Google Scholar 

  15. Sharma S, Singh M, Sharma PL (2012) Ameliorative effect of daidzein: a caveolin-1 inhibitor in vascular endothelium dysfunction induced by ovariectomy. Indian J Exp Biol 50:28–34

    CAS  PubMed  Google Scholar 

  16. Li WL, Yu SP, Ogle ME, Ding XS, Wei L (2008) Enhanced neurogenesis and cell migration following focal ischemia and peripheral stimulation in mice. Dev Neurobiol 68:1474–1486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ashwal S, Tone B, Tian HR, Cole DJ, Pearce WJ (1998) Core and penumbral nitric oxide synthase activity during cerebral ischemia and reperfusion. Stroke 29:1037–1046 (discussion 1047)

    Article  CAS  PubMed  Google Scholar 

  18. Kim YR, Kim HN, Ahn SM, Choi YH, Shin HK, Choi BT (2014) Electroacupuncture promotes post-stroke functional recovery via enhancing endogenous neurogenesis in mouse focal cerebral ischemia. PLoS One 9:e90000

    Article  PubMed  PubMed Central  Google Scholar 

  19. Marlier Q, Verteneuil S, Vandenbosch R, Malgrange B (2015) Mechanisms and functional significance of stroke-induced neurogenesis. Front Neurosci 9:458

    Article  PubMed  PubMed Central  Google Scholar 

  20. Nam SM, Kim JW, Yoo DY, Choi JH, Kim W, Jung HY, Won MH, Hwang IK, Seong JK, Yoon YS (2013) Effects of treadmill exercise on neural stem cells, cell proliferation, and neuroblast differentiation in the subgranular zone of the dentate gyrus in cyclooxygenase-2 knockout mice. Neurochem Res 38:2559–2569

    Article  CAS  PubMed  Google Scholar 

  21. Luo J, Hu X, Zhang L, Li L, Zheng H, Li M, Zhang Q (2014) Physical exercise regulates neural stem cells proliferation and migration via SDF-1alpha/CXCR4 pathway in rats after ischemic stroke. Neurosci Lett 578:203–208

    Article  CAS  PubMed  Google Scholar 

  22. Hou SW, Wang YQ, Xu M, Shen DH, Wang JJ, Huang F, Yu Z, Sun FY (2008) Functional integration of newly generated neurons into striatum after cerebral ischemia in the adult rat brain. Stroke 39:2837–2844

    Article  CAS  PubMed  Google Scholar 

  23. Ohira K, Furuta T, Hioki H, Nakamura KC, Kuramoto E, Tanaka Y, Funatsu N, Shimizu K, Oishi T, Hayashi M, Miyakawa T, Kaneko T, Nakamura S (2010) Ischemia-induced neurogenesis of neocortical layer 1 progenitor cells. Nat Neurosci 13:173–179

    Article  CAS  PubMed  Google Scholar 

  24. Janowski M, Wagner DC, Boltze J (2015) Stem cell-based tissue replacement after stroke: factual necessity or notorious fiction? Stroke 46:2354–2363

    Article  PubMed  PubMed Central  Google Scholar 

  25. Sun Y, Jin K, Xie L, Childs J, Mao XO, Logvinova A, Greenberg DA (2003) VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest 111:1843–1851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Schanzer A, Wachs FP, Wilhelm D, Acker T, Cooper-Kuhn C, Beck H, Winkler J, Aigner L, Plate KH, Kuhn HG (2004) Direct stimulation of adult neural stem cells in vitro and neurogenesis in vivo by vascular endothelial growth factor. Brain Pathol 14:237–248

    Article  PubMed  Google Scholar 

  27. Thau-Zuchman O, Shohami E, Alexandrovich AG, Leker RR (2010) Vascular endothelial growth factor increases neurogenesis after traumatic brain injury. J Cereb Blood Flow Metab 30:1008–1016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Head BP, Peart JN, Panneerselvam M, Yokoyama T, Pearn ML, Niesman IR, Bonds JA, Schilling JM, Miyanohara A, Headrick J, Ali SS, Roth DM, Patel PM, Patel HH (2010) Loss of caveolin-1 accelerates neurodegeneration and aging. PLoS One 5:e15697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lee MY, Ryu JM, Lee SH, Park JH, Han HJ (2010) Lipid rafts play an important role for maintenance of embryonic stem cell self-renewal. J Lipid Res 51:2082–2089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Park JH, Han HJ (2009) Caveolin-1 plays important role in EGF-induced migration and proliferation of mouse embryonic stem cells: involvement of PI3K/Akt and ERK. Am J Physiol Cell Physiol 297:C935–C944

    Article  CAS  PubMed  Google Scholar 

  31. Du J, Chen X, Liang X, Zhang G, Xu J, He L, Zhan Q, Feng XQ, Chien S, Yang C (2011) Integrin activation and internalization on soft ECM as a mechanism of induction of stem cell differentiation by ECM elasticity. Proc Natl Acad Sci USA 108:9466–9471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Xu L, Guo R, Xie Y, Ma M, Ye R, Liu X (2015) Caveolae: molecular insights and therapeutic targets for stroke. Expert Opin Ther Targets 19:633–650

    Article  CAS  PubMed  Google Scholar 

  33. Baker N, Tuan RS (2013) The less-often-traveled surface of stem cells: caveolin-1 and caveolae in stem cells, tissue repair and regeneration. Stem Cell Res Ther 4:90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Aras AB, Guven M, Akman T, Ozkan A, Sen HM, Duz U, Kalkan Y, Silan C, Cosar M (2015) Neuroprotective effects of daidzein on focal cerebral ischemia injury in rats. Neural Regen Res 10:146–152

    Article  PubMed  PubMed Central  Google Scholar 

  35. Chan PH (2001) Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab 21:2–14

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported partially by the Natural Science Foundation of Zhejiang Province Project (No. Y12H170002) and the Science Technology Bureau of Wenzhou funded project (No. Y20140677). We also appreciate the great technical assistance provided by the Experimental Animal Center of Wenzhou Medical University and the Laboratory Center of the Second Affiliated Hospital of Wenzhou Medical University & Yuying Children’s Hospital.

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Correspondence to Xiang Chen.

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Zhao, Y., Pang, Q., Liu, M. et al. Treadmill Exercise Promotes Neurogenesis in Ischemic Rat Brains via Caveolin-1/VEGF Signaling Pathways. Neurochem Res 42, 389–397 (2017). https://doi.org/10.1007/s11064-016-2081-z

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