Role of Granulocyte-colony Stimulating Factor in the Protection of Cerebral Vascular Endothelium, White Matter, and Cognition

Author(s): Minghui Tuo, Yunyue Xiao, Yan Xu*, Lisha Wang, Xin Wei, Lei Zhang.

Journal Name: Current Neurovascular Research

Volume 16 , Issue 5 , 2019

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Abstract:

Background: Granulocyte-colony stimulating factor (G-CSF) has protective effects on many neurological diseases. The effects of G-CSF on vascular endothelium and White Matter (WM) injury in Cerebral Small Vessel Disease (CSVD) were explored in this study via a model of spontaneously hypertensive rat (SHR) in order to elucidate the mechanism of G-CSF in Vascular Cognitive Impairment (VCI).

Methods: 24-week-old male SHRs were randomly divided into the treatment group and model group, with the same age Wistar rats as the control group. The novel object recognition test (NORT) and Morris water maze were conducted after 7 days of G-CSF(50ug/kg) or normal saline treatment to examine their non-spatial and spatial cognitive functions. After that, a transmission electron microscope (TEM) and FLB staining were used to observe the vascular endothelial cell and WM damage. Furthermore, the expression of VEGF, MMP-9, Caspase-3, TUNEL and BrdULaminin in the cortical area was detected by immunostaining methods.

Results: Our results showed that G-CSF promoted the expression of VEGF and BrdU+-Laminin+ endothelial cells, but down-regulated the level of MMP-9, thus significantly repaired the cerebral vascular endothelial cells and perivascular structure in SHR. The WM damage, the expression of caspase-3 and the apoptosis rate decreased after G-CSF treatment. Ultimately, G-CSF improved the non-spatial cognitive function in SHR rather than the spatial cognitive function.

Conclusion: Therefore, our findings indicated that G-CSF might facilitate the improvement of non-spatial cognitive function in CSVD by repairing endothelial cells and alleviating WM damage.

Keywords: Cerebral small vessel disease, granulocyte colony-stimulating factor, spontaneously hypertensive rat, white matter, vascular endothelium, blood-brain barrier, cognitive.

[1]
Jellinger KA. Pathology and pathogenesis of vascular cognitive impairment-a critical update. Front Aging Neurosci 2013; 5: 17.
[http://dx.doi.org/10.3389/fnagi.2013.00017] [PMID: 23596414]
[2]
Dichgans M, Zietemann V. Prevention of vascular cognitive impairment. Stroke 2012; 43(11): 3137-46.
[http://dx.doi.org/10.1161/STROKEAHA.112.651778] [PMID: 22935401]
[3]
Sierra C. Cerebral small vessel disease, cognitive impairment and vascular dementia. Panminerva Med 2012; 54(3): 179-88.
[PMID: 22801435]
[4]
Wardlaw JM, Smith C, Dichgans M. Mechanisms of sporadic cerebral small vessel disease: Insights from neuroimaging. Lancet Neurol 2013; 12(5): 483-97.
[http://dx.doi.org/10.1016/S1474-4422(13)70060-7] [PMID: 23602162]
[5]
Wardlaw JM, Smith EE, Biessels GJ, et al. STandards for ReportIng Vascular changes on nEuroimaging (STRIVE v1). Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 2013; 12(8): 822-38.
[http://dx.doi.org/10.1016/S1474-4422(13)70124-8] [PMID: 23867200]
[6]
Arboix A, Blanco-Rojas L, Martí-Vilalta JL. Advancements in understanding the mechanisms of symptomatic lacunar ischemic stroke: Translation of knowledge to prevention strategies. Expert Rev Neurother 2014; 14(3): 261-76.
[http://dx.doi.org/10.1586/14737175.2014.884926] [PMID: 24490992]
[7]
Bath PM, Wardlaw JM. Pharmacological treatment and prevention of cerebral small vessel disease: A review of potential interventions. Int J Stroke 2015; 10(4): 469-78.
[http://dx.doi.org/10.1111/ijs.12466] [PMID: 25727737]
[8]
Xiao BG, Lu CZ, Link H. Cell biology and clinical promise of G-CSF: Immunomodulation and neuroprotection. J Cell Mol Med 2007; 11(6): 1272-90.
[http://dx.doi.org/10.1111/j.1582-4934.2007.00101.x] [PMID: 18205701]
[9]
Liew HK, Kuo JS, Wang JY, Pang CY. Granulocyte-colony stimulating factor increases cerebral blood flow via a no surge mediated by Akt/eNOS pathway to reduce ischemic injury. Sci World J 2015.2015657932
[http://dx.doi.org/10.1155/2015/657932] [PMID: 26146654]
[10]
Lee ST, Chu K, Jung KH, et al. Granulocyte colony-stimulating factor enhances angiogenesis after focal cerebral ischemia. Brain Res 2005; 1058(1-2): 120-8.
[http://dx.doi.org/10.1016/j.brainres.2005.07.076] [PMID: 16150422]
[11]
Duelsner A, Gatzke N, Glaser J, et al. Granulocyte colony-stimulating factor improves cerebrovascular reserve capacity by enhancing collateral growth in the circle of Willis. Cerebrovasc Dis 2012; 33(5): 419-29.
[http://dx.doi.org/10.1159/000335869] [PMID: 22456527]
[12]
Su J, Zhou H, Tao Y, et al. G-CSF protects human brain vascular endothelial cells injury induced by high glucose, free fatty acids and hypoxia through MAPK and Akt signaling. PLoS One 2015; 10(4)e0120707
[http://dx.doi.org/10.1371/journal.pone.0120707] [PMID: 25849550]
[13]
van Dijk EJ, Breteler MM, Schmidt R, et al. CASCADE Consortium. The association between blood pressure, hypertension, and cerebral white matter lesions: Cardiovascular determinants of dementia study. Hypertension 2004; 44(5): 625-30.
[http://dx.doi.org/10.1161/01.HYP.0000145857.98904.20] [PMID: 15466662]
[14]
Kaiser D, Weise G, Möller K, et al. Spontaneous white matter damage, cognitive decline and neuroinflammation in middle-aged hypertensive rats: An animal model of early-stage cerebral small vessel disease. Acta Neuropathol Commun 2014; 2: 169.
[http://dx.doi.org/10.1186/s40478-014-0169-8] [PMID: 25519173]
[15]
Verjugina NI, Chimagomedova AS, Starovoitova IM, Levin OS. Endothelial dysfunction in chronic vascular encephalopathy. Zh Nevrol Psikhiatr Im SS Korsakova 2017; 117(6. Vyp. 2): 73-80.
[http://dx.doi.org/10.17116/jnevro20171176273-80]
[16]
Poggesi A, Pasi M, Pescini F, Pantoni L, Inzitari D. Circulating biologic markers of endothelial dysfunction in cerebral small vessel disease: A review. J Cereb Blood Flow Metab 2016; 36(1): 72-94.
[http://dx.doi.org/10.1038/jcbfm.2015.116] [PMID: 26058695]
[17]
Maillard P, Seshadri S, Beiser A, et al. Effects of systolic blood pressure on white-matter integrity in young adults in the Framingham Heart Study: A cross-sectional study. Lancet Neurol 2012; 11(12): 1039-47.
[http://dx.doi.org/10.1016/S1474-4422(12)70241-7] [PMID: 23122892]
[18]
Barr TL, Latour LL, Lee KY, et al. Blood-brain barrier disruption in humans is independently associated with increased matrix metalloproteinase-9. Stroke 2010; 41(3): e123-8.
[http://dx.doi.org/10.1161/STROKEAHA.109.570515] [PMID: 20035078]
[19]
Menzie-Suderam JM, Mohammad-Gharibani P, Modi J, et al. Granulocyte-colony stimulating factor protects against endoplasmic reticulum stress in an experimental model of stroke. Brain Res 2018; 1682: 1-13.
[http://dx.doi.org/10.1016/j.brainres.2017.12.022] [PMID: 29277709]
[20]
Prakash A, Medhi B, Chopra K. Granulocyte colony stimulating factor (GCSF) improves memory and neurobehavior in an amyloid-β induced experimental model of Alzheimer’s disease. Pharmacol Biochem Behav 2013; 110: 46-57.
[http://dx.doi.org/10.1016/j.pbb.2013.05.015] [PMID: 23756182]
[21]
dela Peña IC, Yoo A, Tajiri N, et al. Granulocyte colony-stimulating factor attenuates delayed tPA-induced hemorrhagic transformation in ischemic stroke rats by enhancing angiogenesis and vasculogenesis. J Cereb Blood Flow Metab 2015; 35(2): 338-46.
[http://dx.doi.org/10.1038/jcbfm.2014.208] [PMID: 25425079]
[22]
Natori T, Sata M, Washida M, Hirata Y, Nagai R, Makuuchi M. G-CSF stimulates angiogenesis and promotes tumor growth: Potential contribution of bone marrow-derived endothelial progenitor cells. Biochem Biophys Res Commun 2002; 297(4): 1058-61.
[http://dx.doi.org/10.1016/S0006-291X(02)02335-5] [PMID: 12359263]
[23]
Wei X, Xu Y, Jin Y, Feng H, Xiao Y, Dong S. Granulocyte colony-stimulating factor attenuates blood-brain barrier damage and improves cognitive function in spontaneously hypertensive rats. CNS Neurol Disord Drug Targets 2017; 16(7): 781-8.
[http://dx.doi.org/10.2174/1871527316666170207155730] [PMID: 28176642]
[24]
Sun BL, He MQ, Han XY, et al. Intranasal delivery of granulocyte colony-stimulating factor enhances its neuroprotective effects against ischemic brain injury in rats. Mol Neurobiol 2016; 53(1): 320-30.
[http://dx.doi.org/10.1007/s12035-014-8984-2] [PMID: 25432887]
[25]
Zhang ZG, Zhang L, Tsang W, et al. Correlation of VEGF and angiopoietin expression with disruption of blood-brain barrier and angiogenesis after focal cerebral ischemia. J Cereb Blood Flow Metab 2002; 22(4): 379-92.
[http://dx.doi.org/10.1097/00004647-200204000-00002] [PMID: 11919509]
[26]
Lennmyr F, Ata KA, Funa K, Olsson Y, Terént A. Expression of vascular endothelial growth factor (VEGF) and its receptors (Flt-1 and Flk-1) following permanent and transient occlusion of the middle cerebral artery in the rat. J Neuropathol Exp Neurol 1998; 57(9): 874-82.
[http://dx.doi.org/10.1097/00005072-199809000-00009] [PMID: 9737551]
[27]
Ohki Y, Heissig B, Sato Y, et al. Granulocyte colony-stimulating factor promotes neovascularization by releasing vascular endothelial growth factor from neutrophils. FASEB J 2005; 19(14): 2005-7.
[http://dx.doi.org/10.1096/fj.04-3496fje] [PMID: 16223785]
[28]
Jung KH, Chu K, Lee ST, et al. Granulocyte colony-stimulating factor stimulates neurogenesis via vascular endothelial growth factor with STAT activation. Brain Res 2006; 1073-1074: 190-201.
[http://dx.doi.org/10.1016/j.brainres.2005.12.037] [PMID: 16423324]
[29]
Chu H, Tang Y, Dong Q. Protection of granulocyte-colony stimulating factor to hemorrhagic brain injuries and its involved mechanisms: Effects of vascular endothelial growth factor and aquaporin-4. Neuroscience 2014; 260: 59-72.
[http://dx.doi.org/10.1016/j.neuroscience.2013.12.017] [PMID: 24355496]
[30]
Li DD, Song JNH, Huang H, et al. The roles of MMP-9/TIMP-1 in cerebral edema following experimental acute cerebral infarction in rats. Neurosci Lett 2013; 550: 168-72.
[http://dx.doi.org/10.1016/j.neulet.2013.06.034] [PMID: 23819982]
[31]
Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 2006; 69(3): 562-73.
[http://dx.doi.org/10.1016/j.cardiores.2005.12.002] [PMID: 16405877]
[32]
Newby AC. Matrix metalloproteinases regulate migration, proliferation, and death of vascular smooth muscle cells by degrading matrix and non-matrix substrates. Cardiovasc Res 2006; 69(3): 614-24.
[http://dx.doi.org/10.1016/j.cardiores.2005.08.002] [PMID: 16266693]
[33]
Lin Z, Wang Z, Li G, Li B, Xie W, Xiang D. Fibulin-3 may improve vascular health through inhibition of MMP-2/9 and oxidative stress in spontaneously hypertensive rats. Mol Med Rep 2016; 13(5): 3805-12.
[http://dx.doi.org/10.3892/mmr.2016.5036] [PMID: 27035767]
[34]
Sevimli S, Diederich K, Strecker JK, et al. Endogenous brain protection by granulocyte-colony stimulating factor after ischemic stroke. Exp Neurol 2009; 217(2): 328-35.
[http://dx.doi.org/10.1016/j.expneurol.2009.03.018] [PMID: 19332060]
[35]
Miyamoto N, Pham LD, Seo JH, Kim KW, Lo EH, Arai K. Crosstalk between cerebral endothelium and oligodendrocyte. Cell Mol Life Sci 2014; 71(6): 1055-66.
[http://dx.doi.org/10.1007/s00018-013-1488-9] [PMID: 24132511]
[36]
Rajani RM, Williams A. Endothelial cell-oligodendrocyte interactions in small vessel disease and aging. Clin Sci (Lond) 2017; 131(5): 369-79.
[http://dx.doi.org/10.1042/CS20160618] [PMID: 28202749]
[37]
Kadota R, Koda M, Kawabe J, et al. Granulocyte colony-stimulating factor (G-CSF) protects oligodendrocyte and promotes hindlimb functional recovery after spinal cord injury in rats. PLoS One 2012; 7(11)e50391
[http://dx.doi.org/10.1371/journal.pone.0050391] [PMID: 23209732]
[38]
Liu XY, Gonzalez-Toledo ME, Fagan A, et al. Stem cell factor and granulocyte colony-stimulating factor exhibit therapeutic effects in a mouse model of CADASIL. Neurobiol Dis 2015; 73: 189-203.
[http://dx.doi.org/10.1016/j.nbd.2014.09.006] [PMID: 25251607]
[39]
Li L, Klebe D, Doycheva D, et al. G-CSF ameliorates neuronal apoptosis through GSK-3β inhibition in neonatal hypoxia-ischemia in rats. Exp Neurol 2015; 263: 141-9.
[http://dx.doi.org/10.1016/j.expneurol.2014.10.004] [PMID: 25448005]


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VOLUME: 16
ISSUE: 5
Year: 2019
Page: [425 - 432]
Pages: 8
DOI: 10.2174/1567202616666191029115113
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