Mechanisms of neurogenesis and angiogenesis in ischaemic stroke: literature review

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Scientific achievements of recent decades indicate that neurogenesis and angiogenesis are interrelated processes in the struggle for functional recovery after ischaemic stroke. This literature review presents current data on the neurovascular interactions in ischaemic stroke, and describes the role of signalling molecules and growth factors in the regulation of neurogenesis and angiogenesis, which are crucial for neuronal survival and neuroplasticity. The authors conducted a literature search for abnormal neuroblast migration into the ischaemic penumbra and the role of signalling molecules, molecular targets of angiogenesis, and role of endogenous growth factors and neurochemical markers in post-stroke vascular regulation in acute cerebral ischaemia. Relevant keywords were entered into the PubMed and Google Scholar search engines, as well as Scopus, Web of Science, MedLine, The Cochrane Library, EMBASE, Global Health, CyberLeninka, eLibrary, and other databases.

Despite promising results obtained in animal models, and the data from clinical studies, deeper interrelationships between molecular and cellular interactions of neurogenesis and angiogenesis are still not entirely clear. Further study and understanding of complex interactions between neurogenesis and angiogenesis is needed to find targets for exogenous growth factor administration and changes in endogenous molecule expression for treatment of ischaemic brain injury.

About the authors

Ekaterina S. Koroleva

Siberian State Medical University

Author for correspondence.
ORCID iD: 0000-0003-1911-166X

Cand. Sci. (Med.), Assoc. prof., Department of neurology and neurosurgery

Russian Federation, 634055, Tomsk, Moskovsky trakt, 2

Valentina M. Alifirova

Siberian State Medical University

ORCID iD: 0000-0002-4140-3223

D. Sci. (Med.), Professor, Head, Department of neurology and neurosurgery

Russian Federation, 634055, Tomsk, Moskovsky trakt, 2


  1. Piradov M.A., Maksimova M.Yu., Tanashyan M.M. Stroke: step by step instructions. Moscow: GEOTAR-Media; 2019. (In Russ.)
  2. Wittchen H.U., Jacobi F., Rehm J. et al. The size and burden of mental disorders and other disorders of the brain in Europe 2010. Eur Neuropsychopharmacol. 2011;21(9):655–679. doi: 10.1016/j.euroneuro.2011.07.018. PMID: 21896369.
  3. Go A.S., Mozaffarian D., Roger V.L. et al. Heart disease and stroke statistics — 2013 Update: a report from the American Heart Association. Circulation. 2013;127(1):143–152. doi: 10.1161/CIR.0b013e31828124ad. PMID: 23239837.
  4. Wang B., Jin K. Current perspectives on the link between neuroinflammation and neurogenesis. Metab Brain Dis. 2015;30(2):355–365. doi: 10.1007/s11011-014-9523-6. PMID: 24623361.
  5. Nemirovich-Danchenko N.M., Khodanovich M.Yu. New neurons in the post-ischemic and injured brain: migrating or resident? Front Neurosci. 2019;13:588. doi: 10.3389/fnins.2019.005887. PMID: 31275097.
  6. Mizrak D., Levitin H.M., Delgado A.C. et al. Single-cell analysis of regional differences in adult СВЗ neural stem cell lineages. Cell Rep. 2019;26(2):394-406.e5. doi: 10.1016/j.celrep.2018.12.044. PMID: 30625322.
  7. Jin K., Wang X., Xie L. et al. Evidence for stroke-induced neurogenesis in the human brain. Proc Natl Acad Sci USA. 2006;103(35):13198–13202. doi: 10.1073/pnas.0603512103. PMID: 16924107.
  8. Thored P., Arvidsson A., Cacci E. et al. Persistent production of neurons from adult brain stem cells during recovery after stroke. Stem Cells. 2006;24(3):739–747. doi: 10.1634/stemcells.2005-0281. PMID: 16210404.
  9. Carmeliet P., Jain R.K. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473(7347):298–307. doi: 10.1038/nature10144. PMID: 21593862.
  10. Ruan L., Wang B., ZhuGe Q., Jin K. Coupling of neurogenesis and angiogenesis after ischemic stroke. Brain Res. 2015;1623:166–173. doi: 10.1016/j.brainres.2015.02.042. PMID: 25736182.
  11. Gomazkov O.A. Neurogenesis as an adaptive function of the brain. Moscow: Icarus; 2013. (In Russ.)
  12. Tang H., Wang Y., Xie L. et al. Effect of neural precursor proliferation level on neurogenesis in rat brain during aging and after focal ischemia. Neurobiol Aging. 2009;30(2):299–308. doi: 10.1016/j.neurobiolaging.2007.06.004. PMID: 17644223.
  13. Zhang R.L., Zhang Z.G., Lu M. et al. Reduction of the cell cycle length by decreasing G1 phase and cell cycle reentry expand neuronal progenitor cells in the subventricular zone of adult rat after stroke. J Cereb Blood Flow Metab. 2006;26(6):857–863. doi: 10.1038/sj.jcbfm.9600237. PMID: 16251885.
  14. Zhang R.L., Chopp M., Roberts C. et al. Stroke increases neural stem cells and angiogenesis in the neurogenic niche of the adult mouse. PLoS One. 2014;9(12):e113972. doi: 10.1371/journal.pone.0113972. PMID: 25437857.
  15. Faiz M., Sachewsky N., Gascón S. et al. Adult neural stem cells from the subventricular zone give rise to reactive astrocytes in the cortex after stroke. Cell Stem Cell. 2015;17(5):624–634. doi: 10.1016/j.stem.2015.08.002. PMID: 26456685.
  16. Sakamoto M., Kageyama R., Imayoshi I. The functional significance of newly born neurons integrated into olfactory bulb circuits. Front Neurosci. 2014;8:121. doi: 10.3389/fnins.2014.00121. PMID: 24904263.
  17. Le Magueresse C., Alfonso J., Bark C. et al. Subventricular zone-derived neuroblasts use vasculature as a scaffold to migrate radially to the cortex in neonatal mice. Cereb Cortex. 2012;22(10):2285–2296. doi: 10.1093/cercor/bhr302. PMID: 22095212.
  18. Fuentealba L.C., Rompani S.B., Parraguez J.I. et al. Embryonic origin of postnatal neural stem cells. Cell. 2015;161(7):1644–1655. doi: 10.1016/j.cell.2015.05.041. PMID: 26091041.
  19. Lim D.A., Alvarez-Buylla A. The adult ventricular — subventricular zone and olfactory bulb neurogenesis. Cold Spring Harb Perspect Biol. 2016;8(5):a018820. doi: 10.1101/cshperspect.a018820. PMID: 27048191.
  20. Wan F., Bai H.J., Liu J.Q. et al. Proliferation and glia-directed differentiation of neural stem cells in the subventricular zone of the lateral ventricle and the migratory pathway to the lesions after cortical devascularization of adult rats. BioMed Res Int. 2016;2016: 3625959. doi: 10.1155/2016/3625959. PMID: 27294116.
  21. Thored P., Wood J., Arvidsson A. et al. Long-term neuroblast migration along blood vessels in an area with transient angiogenesis and increased vascularization after stroke. Stroke. 2007;38(11):3032–3039. doi: 10.1161/STROKEAHA.107.488445. PMID: 17901386.
  22. Sawada M., Matsumoto M., Sawamoto K. Vascular regulation of adult neurogenesis under physiological and pathological conditions. Front Neurosci. 2014;8:53. doi: 10.3389/fnins.2014.00053. PMID: 24672424.
  23. Kokovay E., Goderie S., Wang Y. et al. Adult SVZ lineage cells home to and leave the vascular niche via differential responses to SDF1/CXCR4 signaling. Cell Stem Cell. 2010;7(2):163–173. doi: 10.1016/j.stem.2010.05.019. PMID: 20682445.
  24. Wang B., Jin K. Current perspectives on the link between neuroinflammation and neurogenesis. Metab Brain Dis. 2015;30(2):355–365. doi: 10.1007/s11011-014-9523-6. PMID: 24623361.
  25. Barkho B.Z., Munoz A.E., Li X. et al. Endogenous matrix metalloproteinase (MMP)-3 and MMP-9 promote the differentiation and migration of adult neural progenitor cells in response to chemokines. Stem Cells. 2008;26(12):3139–3149. doi: 10.1634/stemcells.2008-0519. PMID: 18818437.
  26. Naylor M., Bowen K.K., Sailor K.A. et al. Preconditioning-induced ische-mic tolerance stimulates growth factor expression and neurogenesis in adult rat hippocampus. Neurochem Int. 2005;47(8):565–572. doi: 10.1016/j.neuint.2005.07.003. PMID: 16154234.
  27. Benington L., Rajan G., Locher C., Lim L.Y. Fibroblast Growth Factor 2 —a review of stabilisation approaches for clinical applications. Pharmaceutics. 2020;12(6):508. doi: 10.3390/pharmaceutics12060508. PMID: 32498439.
  28. Simonato M., Zucchini S. Neurotrophic factors. Fibroblast Growth Factor-2. Encyclopedia of Basic Epilepsy Research. Elsevier, 2009:916–921. doi: 10.1016/B978-012373961-2.00252-6.
  29. Larpthaveesarp A., Ferriero D.M., Gonzalez F.F. Growth factors for the treatment of ischemic brain injury (growth factor treatment). Brain Sci. 2015;5(2):165–177. doi: 10.3390/brainsci5020165. PMID: 25942688.
  30. Wrigley S., Arafa D., Tropea D. Insulin-like growth factor 1: at the crossroads of brain development and aging. Front Cell Neurosci. 2017;11:14. doi: 10.3389/fncel.2017.00014. PMID: 28203146.
  31. Rosenzweig S.A. The continuing evolution of insulin-like growth factor signaling. F1000Res. 2020;9:F1000 Faculty Rev-205. doi: 10.12688/f1000research.22198.1. PMID: 32226608.
  32. Genis L., Davila D., Fernandez S. et al. Astrocytes require insulin-like growth factor I to protect neurons against oxidative injury. F1000Res. 2014;3:28. doi: 10.12688/f1000research.3-28.v2. PMID: 24715976.
  33. Serhan A., Boddeke E., Kooijman R. Insulin-like growth factor-1 is neuroprotective in aged rats with ischemic stroke. Front Aging Neurosci. 2019;11:349. doi: 10.3389/fnagi.2019.00349. PMID: 31920629.
  34. Shaheen H., Sobhy S., El Mously S. et al. Insulin-like growth factor-1 in acute ischemic stroke. Egypt J Neurol Psychiatr Neurosurg. 2018;54(1):42. doi: 10.1186/s41983-018-0042-y. PMID: 30595648.
  35. Tang J.H., Ma L.L., Yu T.X. et al. Insulin-like growth factor-1 as a prognostic marker in patients with acute ischemic stroke. PLoS One. 2014;9(6):e99186. doi: 10.1371/journal.pone.0099186. PMID: 24911265.
  36. Okazaki H., Beppu H., Mizutani K. et al. Changes in serum growth factors in stroke rehabilitation patients and their relation to hemiparesis improvement. J Stroke Cerebrovasc Dis. 2014;23(6):1703–1708. doi: 10.1016/j.jstrokecerebrovasdis.2014.01.015. PMID: 24768137.
  37. Zheng H.Q., Zhang L.Y., Luo J. et al. Physical exercise promotes recovery of neurological function after ischemic stroke in rats. Int J Molec Sci. 2014;15(6):10974–10988. doi: 10.3390/ijms150610974. PMID: 24945308.
  38. Gregory S.M., Spiering B.A., Alemany J.A. et al. Exercise-induced insulin-like growth factor I system concentrations after training in women. Med Sci Sports Exerc. 2013;45(3):420–428. doi: 10.1249/MSS.0b013e3182750bd4. PMID: 23034644.
  39. Zhu W., Fan Y., Hao Q. et al. Postischemic IGF-1 gene transfer promotes neurovascular regeneration after experimental stroke. J Cereb Blood Flow Metab. 2009;29(9):1528–1537. doi: 10.1038/jcbfm.2009.75. PMID: 19513085.
  40. Liu W., Wang X., O’Connor M. et al. Brain-derived neurotrophic factor and its potential therapeutic role in stroke comorbidities. Neural Plast. 2020;2020:1969482. doi: 10.1155/2020/1969482. PMID: 32399020.
  41. Liu P.Z., Nusslock R. Exercise-mediated neurogenesis in the hippocampus via BDNF. Front Neurosci. 2018;12:52. doi: 10.3389/fnins.2018.00052. PMID: 29467613.
  42. Balkaya M., Cho S. Genetics of stroke recovery: BDNF val66met polymorphism in stroke recovery and its interaction with aging. Neurobiol Dis. 2019;126:36–46. doi: 10.1016/j.nbd.2018.08.009. PMID: 30118755.
  43. Yoshii A., Constantine-Paton M. Post-synaptic BDNF-TrkB signaling in synapse maturation, plasticity and disease. Dev Neurobiol. 2010;70(5):304–322. doi: 10.1002/dneu.20765. PMID: 20186705.
  44. Phillips C., Baktir M.A., Srivatsan M., Salehi A. Neuroprotective effects of physical activity on the brain: a closer look at trophic factor signaling. Front Cell Neurosci. 2014;8:170. doi: 10.3389/fncel.2014.00170. PMID: 24999318.
  45. Zhao H., Alam A., San C.Y. et al. Molecular mechanisms of brain-derived neurotrophic factor in neuro-protection: Recent developments. Brain Res. 2017;1665:1–21. doi: 10.1016/j.brainres.2017.03.029. PMID: 28396009.
  46. Ramos-Cejudo J., Gutiérrez-Fernández M., Otero-Ortega L. et al. Brain-derived neurotrophic factor administration mediated oligodendrocyte differentiation and myelin formation in subcortical ischemic stroke. Stroke. 2015;46(1):221–228. doi: 10.1161/STROKEAHA.114.006692. PMID: 25395417.
  47. Li S.T., Pan J., Hua X.M. et al. Endothelial nitric oxide synthase protects neurons against ischemic injury through regulation of brain- derived neurotro-phic factor expression. CNS Neurosci Ther. 2014;20(2):154–164. doi: 10.1111/cns.12182. PMID: 24397751.
  48. Kotlęga D., Peda B., Zembroń-Łacny A. et al. The role of brain-derived neurotrophic factor and its single nucleotide polymorphisms in stroke patients. Neurol Neurochir Pol. 2017;51(3):240–246. doi: 10.1016/j.pjnns.2017.02.008. PMID: 28291539.
  49. Greenberg D.A., Jin K. Vascular endothelial growth factors (VEGFs) and stroke. Cell Mol Life Sci. 2013;70(10):1753–1761. doi: 10.1007/s00018-013-1282-8. PMID: 23475070.
  50. Jin K.L., Mao X.O., Nagayama T. et al. Induction of vascular endothelial growth factor receptors and phosphatidylinositol 3’-kinase/Akt signaling by global cerebral ischemia in the rat. Neuroscience. 2000;100(4):713–717. doi: 10.1016/s0306-4522(00)00331-6. PMID: 11036205.
  51. Jiang C., Zuo F., Wang Y. et al. Progesterone changes VEGF and BDNF expression and promotes neurogenesis after ischemic stroke. Mol Neurobiol. 2017;54:571–581. doi: 10.1007/s12035-015-9651-y. PMID: 26746666.
  52. Horie N., Pereira M.P., Niizuma K. et al. Transplanted stem cell-secreted vascular endothelial growth factor effects poststroke recovery, inflammation, and vascular repair. Stem Cells. 2011;29(2):274–285. doi: 10.1002/stem.584. PMID: 21732485.
  53. Harms K.M., Lu L., Cunningham L.A. Murine neural stem/progenitor cells protect neurons against ischemia by HIF-1alpha-regulated VEGF signaling. PLoS One. 2010;5(3):e9767. doi: 10.1371/journal.pone.0009767. PMID: 20339541.
  54. Cardenas-Rivera A., Campero-Romero A.N., Heras-Romero Y. et al. Early post-stroke activation of vascular endothelial growth factor receptor 2 hinders the receptor 1-dependent neuroprotection afforded by the endogenous ligand. Front Cell Neurosci. 2019;13:270. doi: 10.3389/fncel.2019.00270. PMID: 31312121.
  55. Freitas-Andrade M., Raman-Nair J., Lacoste B. Structural and functional remodeling of the brain vasculature following stroke. Front Physiol. 2020;11:948. doi: 10.3389/fphys.2020.00948. PMID: 32848875.
  56. Font M.A., Arboix A., Krupinski J. Angiogenesis, neurogenesis and neuroplasticity in ischemic stroke. Curr Cardiol Rev. 2010;6(3):238–244. doi: 10.2174/157340310791658802. PMID: 21804783.
  57. Ergul A., Alhusban A., Fagan S.C. Angiogenesis: a harmonized target for recovery after stroke. Stroke. 2012;43(8):2270–2274. doi: 10.1161/STROKEAHA.111.642710. PMID: 22618382.
  58. Coletta C., Papapetropoulos A., Erdelyi K. et al. Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxation. Proc Natl Acad Sci USA. 2012;109(23):9161–9166. doi: 10.1073/pnas.1202916109. PMID: 22570497.
  59. Wang F., Cao Y., Ma L. et al. Dysfunction of cerebrovascular endothelial cells: prelude to vascular dementia. Front Aging Neurosci. 2018;10:376. doi: 10.3389/fnagi.2018.00376. PMID: 30505270.
  60. Kimmel E.R., Al Kasab S., Harvey J.B. et al. Absence of collaterals is associated with larger infarct volume and worse outcome in patients with large vessel occlusion and mild symptoms. J Stroke Cerebrovasc Dis. 2019;28(7):1987–1992. doi: 10.1016/j.jstrokecerebrovasdis.2019.03.032. PMID: 31036341.
  61. Nannoni S., Cereda C.W., Sirimarco G. et al. Collaterals are a major determinant of the core but not the penumbra volume in acute ischemic stroke. Neuroradiology. 2019;61(9):971–978. doi: 10.1007/s00234-019-02224-x. PMID: 31123760.
  62. Zhang H., Chalothorn D., Faber J.E. Collateral vessels have unique endothelial and smooth muscle cell phenotypes. Int J Mol Sci. 2019;20(15):3608. doi: 10.3390/ijms20153608. PMID: 31344780.
  63. Hiroi Y., Noma K., Kim H.H. et al. Neuroprotection mediated by upregulation of endothelial nitric oxide synthase in Rho-associated, coiled-coil-containing Kinase 2 deficient mice. Circ J. 2018;82(4):1195–1204. doi: 10.1253/circj.CJ-17-0732. PMID: 29353861.
  64. Khaibullina A.A., Rosenstein J.M., Krum J.M. Vascular endothelial growth factor promotes neurite maturation in primary CNS neuronal cultures. Brain Res Dev Brain Res. 2004;148(1):59–68. doi: 10.1016/j.devbrainres.2003.09.022. PMID: 14757519.
  65. Sobrino T., Perez-Mato M., Brea D. et al. Temporal profile of molecular signatures associated with circulating endothelial progenitor cells in humanischemic stroke. J Neurosci Res. 2012;90(9):1788–1793. doi: 10.1002/jnr.23068. PMID: 22513751.
  66. Lacar B., Herman P., Platel J.C. et al. Neural progenitor cells regulate capillary blood flow in the postnatal subventricular zone. J Neurosci. 2012;32(46):16435–16448. doi: 10.1523/JNEUROSCI.1457-12.2012. PMID: 23152626.
  67. Esquiva G., Grayston A., Rosell A. Revascularization and endothelial progenitor cells in stroke Revascularization and endothelial progenitor cells in stroke. Am J Physiol Cell Physiol. 2018;315(5):C664–C674. doi: 10.1152/ajpcell.00200.2018. PMID: 30133323.
  68. Hatakeyama M., Ninomiya I., Kanazawa M. Angiogenesis and neuronal remodeling after ischemic stroke. Neural Regen Res. 2020;15(1):16–19. doi: 10.4103/1673-5374.264442. PMID: 31535636.
  69. Tata M., Ruhrberg C. Cross-talk between blood vessels and neural progenitors in the developing brain. Neuronal Signal. 2018;2(1):NS20170139. doi: 10.1042/NS20170139. PMID: 32714582.
  70. Stanimirovic D.B., Sandhu J.K., Costain W.J. Emerging technologies for delivery of biotherapeutics and gene therapy across the blood-brain barrier. Bio-Drugs. 2018;32(6):547–559. doi: 10.1007/s40259-018-0309-y. PMID: 30306341.
  71. Kanazawa M., Takahashi T., Ishikawa M. et al. Angiogenesis in the ischemic core: a potential treatment target? J Cereb Blood Flow Metab. 2019;39(5):753–769. doi: 10.1177/0271678X19834158. PMID: 30841779.

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Copyright (c) 2021 Koroleva E.S., Alifirova V.M.

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