Skip to main content
Top
Published in: Translational Stroke Research 4/2020

Open Access 01-08-2020 | Stroke | Original Article

Association of High Serum Levels of Growth Factors with Good Outcome in Ischemic Stroke: a Multicenter Study

Authors: Tomás Sobrino, Manuel Rodríguez-Yáñez, Francisco Campos, Ramón Iglesias-Rey, Mónica Millán, Natalia Pérez de la Ossa, Antonio Dávalos, Raquel Delgado-Mederos, Alejandro Martínez-Domeño, Joan Martí-Fábregas, Mar Castellanos, Joaquín Serena, Aida Lago, Exuperio Díez-Tejedor, José Castillo

Published in: Translational Stroke Research | Issue 4/2020

Login to get access

Abstract

The main objective of this research work was to study the association of serum levels of growth factors (GF) and SDF-1α with the functional outcome and reduction of lesion volume in ischemic stroke patients. In this multicenter study, 552 patients with non-lacunar stroke (male, 62.1%; mean age, 68.2 ± 11.4) were included within 24 h from symptom onset. The main outcome variable was good functional outcome (modified Rankin Scale [mRS] ≤ 2) at 12 months. Secondary outcome variable was infarct volume (in mL) after 6 ± 3 months. Serum levels of VEGF, Ang-1, G-CSF, BDNF, and SDF-1α were measured by ELISA at admission, 7 ± 1 days, at 3 ± 1 months, and 12 ± 3 months. Except for BDNF, all GF and SDF-1α serum levels showed a peak value at day 7 and remained elevated during the first 3 months (all p < 0.01). High serum levels at day 7 of VEGF (OR, 19.3), Ang-1 (OR, 14.7), G-CSF (OR, 9.6), and SDF-1α (OR, 28.5) were independently associated with good outcome at 12 months (all p < 0.0001). On the other hand, serum levels of VEGF (B, − 21.4), G-CSF (B, − 14.0), Ang-1 (B, − 13.3), and SDF-1α (B, − 44.6) measured at day 7 were independently associated with lesion volume at 6 months (p < 0.01). In summary, high serum levels of VEGF, Ang-1, G-CSF, and SDF-1α at day 7 and 3 months after ischemic stroke are associated with good functional outcome and smaller residual lesion at 1 year of follow-up.
Literature
1.
go back to reference Mensah GA, Sacco RL, Vickrey BG, et al. From data to action: neuroepidemiology informs implementation research for global stroke prevention and treatment. Neuroepidemiology. 2015;45:221–9.PubMedPubMedCentral Mensah GA, Sacco RL, Vickrey BG, et al. From data to action: neuroepidemiology informs implementation research for global stroke prevention and treatment. Neuroepidemiology. 2015;45:221–9.PubMedPubMedCentral
2.
go back to reference Howard G, Goff DC. Population shifts and the future of stroke: forecast of the future burden of stroke. Ann N Y Acad Sci. 2012;1268:14–20.PubMedPubMedCentral Howard G, Goff DC. Population shifts and the future of stroke: forecast of the future burden of stroke. Ann N Y Acad Sci. 2012;1268:14–20.PubMedPubMedCentral
3.
go back to reference Papanagiotor P, White CJ. Endovascular reperfusion strategies for acute stroke. JACC Cardiovasc Interv. 2016;9:307–17. Papanagiotor P, White CJ. Endovascular reperfusion strategies for acute stroke. JACC Cardiovasc Interv. 2016;9:307–17.
4.
go back to reference Calautti C, Baron JC. Functional neuroimaging studies of motor recovery after stroke in adults: a review. Stroke. 2003;34:1553–66.PubMed Calautti C, Baron JC. Functional neuroimaging studies of motor recovery after stroke in adults: a review. Stroke. 2003;34:1553–66.PubMed
5.
go back to reference Ramachandran VS. Plasticity and functional recovery in Neurology. Clin Med. 2005;5:368–73. Ramachandran VS. Plasticity and functional recovery in Neurology. Clin Med. 2005;5:368–73.
7.
go back to reference Carmichael ST. Emergent properties of neural repair: elemental biology to therapeutic concepts. Ann Neurol. 2016;79:895–906.PubMedPubMedCentral Carmichael ST. Emergent properties of neural repair: elemental biology to therapeutic concepts. Ann Neurol. 2016;79:895–906.PubMedPubMedCentral
8.
go back to reference Bang OY, Kim EH, Cha JM, Moon GJ. Adult stem cell therapy for stroke: challenges and progress. J Stroke. 2016;18:256–66.PubMedPubMedCentral Bang OY, Kim EH, Cha JM, Moon GJ. Adult stem cell therapy for stroke: challenges and progress. J Stroke. 2016;18:256–66.PubMedPubMedCentral
9.
go back to reference Sobrino T, Pérez-Montes M, Brea D, Rodríguez-Yáñez M, Blanco M, Castillo J. Temporal profile of molecular signatures associated with circulating endothelial progenitor cells in human ischemic stroke. J Neurosci Res. 2012;90:1788–93.PubMed Sobrino T, Pérez-Montes M, Brea D, Rodríguez-Yáñez M, Blanco M, Castillo J. Temporal profile of molecular signatures associated with circulating endothelial progenitor cells in human ischemic stroke. J Neurosci Res. 2012;90:1788–93.PubMed
10.
go back to reference Gutiérrez-Fernández M, Fuentes B, Rodríguez-Frutos B, Ramos-Cejudo J, Vallejo-Cremade MT, Díez-Tejedor E. Trophic factors and cell therapy to stimulate brain repair after ischaemic stroke. J Cell Mol Med. 2012;16:2280–90.PubMedPubMedCentral Gutiérrez-Fernández M, Fuentes B, Rodríguez-Frutos B, Ramos-Cejudo J, Vallejo-Cremade MT, Díez-Tejedor E. Trophic factors and cell therapy to stimulate brain repair after ischaemic stroke. J Cell Mol Med. 2012;16:2280–90.PubMedPubMedCentral
11.
go back to reference 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;46:221–8.PubMed 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;46:221–8.PubMed
12.
go back to reference Peplow PV. Growth factor- and cytokine-stimulated endothelial progenitor cells in post-ischemic cerebral neovascularization. Neural Regen Res. 2014;9:1425–9.PubMedPubMedCentral Peplow PV. Growth factor- and cytokine-stimulated endothelial progenitor cells in post-ischemic cerebral neovascularization. Neural Regen Res. 2014;9:1425–9.PubMedPubMedCentral
13.
go back to reference Chan SJ, Love C, Spector M, Cool SM, Nurcombe V, Lo EH. Endogenous regeneration: engineering factors for stroke. Neurochem Int. 2017;107:57-65. Chan SJ, Love C, Spector M, Cool SM, Nurcombe V, Lo EH. Endogenous regeneration: engineering factors for stroke. Neurochem Int. 2017;107:57-65.
14.
go back to reference Huang X, Liu Y, Bai S, Peng L, Zhang B, Lu H. Granulocyte colony stimulating factor therapy for stroke: a pairwise meta-analysis of randomized controlled trial. PLoS ONE. 2017;12:e0175774.PubMedPubMedCentral Huang X, Liu Y, Bai S, Peng L, Zhang B, Lu H. Granulocyte colony stimulating factor therapy for stroke: a pairwise meta-analysis of randomized controlled trial. PLoS ONE. 2017;12:e0175774.PubMedPubMedCentral
15.
go back to reference European Stroke Organisation (ESO) Executive Committee; ESO Writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis. 2008;25:457–507. European Stroke Organisation (ESO) Executive Committee; ESO Writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis. 2008;25:457–507.
16.
go back to reference Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24:35–41.PubMed Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24:35–41.PubMed
17.
go back to reference Qiao HJ, Li ZZ, Wang LM, Sun W, Yu JC, Wang B. Association of lower serum brain-derived neurotrophic factor levels with larger infarcts volumes in acute ischemic stroke. J Neuroimmunol. 2017;307:69–73.PubMed Qiao HJ, Li ZZ, Wang LM, Sun W, Yu JC, Wang B. Association of lower serum brain-derived neurotrophic factor levels with larger infarcts volumes in acute ischemic stroke. J Neuroimmunol. 2017;307:69–73.PubMed
18.
go back to reference Zhao H, Alam A, San CY, et al. Molecular mechanisms of brain-derived neurotrophic factor in neuro-protection: recent developments. Brain Res. 1665;2017:1–21. Zhao H, Alam A, San CY, et al. Molecular mechanisms of brain-derived neurotrophic factor in neuro-protection: recent developments. Brain Res. 1665;2017:1–21.
19.
go back to reference Yong MS, Kim SG, Cheon SH. Effects of skilled reach training with affected forelimb and treadmill exercise on the expression of neurotrophic factor following ischemia-induced brain injury in rats. J Phys Ther Sci. 2017;29:647–50.PubMedPubMedCentral Yong MS, Kim SG, Cheon SH. Effects of skilled reach training with affected forelimb and treadmill exercise on the expression of neurotrophic factor following ischemia-induced brain injury in rats. J Phys Ther Sci. 2017;29:647–50.PubMedPubMedCentral
20.
go back to reference Jiménez I, Sobrino T, Rodríguez-Yáñez M, et al. High serum levels of leptin are associated with post-stroke depression. Psychol Med. 2009;39:1201–9.PubMed Jiménez I, Sobrino T, Rodríguez-Yáñez M, et al. High serum levels of leptin are associated with post-stroke depression. Psychol Med. 2009;39:1201–9.PubMed
21.
go back to reference Yang L, Zhang Z, Sun D, Xu Z, et al. Low serum BDNF may indicate the development of PSD in patients with acute ischemic stroke. Int J Geriatr Psychiatry. 2011;26:495–502.PubMed Yang L, Zhang Z, Sun D, Xu Z, et al. Low serum BDNF may indicate the development of PSD in patients with acute ischemic stroke. Int J Geriatr Psychiatry. 2011;26:495–502.PubMed
22.
go back to reference Béjot Y, Mossiat C, Giroud M, Prigent-Tessier A, Marie C. Circulating and brain BDNF levels in stroke rats. Relevance to clinical studies. PLoS One. 2011;6:e29405.PubMed Béjot Y, Mossiat C, Giroud M, Prigent-Tessier A, Marie C. Circulating and brain BDNF levels in stroke rats. Relevance to clinical studies. PLoS One. 2011;6:e29405.PubMed
23.
go back to reference Rodier M, Quirié A, Prigent-Tessier A, et al. Relevance of post-stroke circulating BDNF levels as a prognostic biomarker of stroke outcome. Impact of rt-PA treatment. PLoS One. 2015;10:e0140668.PubMed Rodier M, Quirié A, Prigent-Tessier A, et al. Relevance of post-stroke circulating BDNF levels as a prognostic biomarker of stroke outcome. Impact of rt-PA treatment. PLoS One. 2015;10:e0140668.PubMed
24.
go back to reference Bus BA, Molendijk ML, Penninx BJ, et al. Determinants of serum brain-derived neurotrophic factor. Psychoneuroendocrinology. 2011;36:228–39.PubMed Bus BA, Molendijk ML, Penninx BJ, et al. Determinants of serum brain-derived neurotrophic factor. Psychoneuroendocrinology. 2011;36:228–39.PubMed
25.
go back to reference Fujimura H, Altar CA, Chen R, et al. Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation. Thromb Haemost. 2002;87:728–34.PubMed Fujimura H, Altar CA, Chen R, et al. Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation. Thromb Haemost. 2002;87:728–34.PubMed
26.
go back to reference Golden E, Emiliano A, Maudsley S, et al. Circulating brain-derived neurotrophic factor and indices of metabolic and cardiovascular health: data from the Baltimore Longitudinal Study of Aging. PLoS One. 2010;5:e10099.PubMedPubMedCentral Golden E, Emiliano A, Maudsley S, et al. Circulating brain-derived neurotrophic factor and indices of metabolic and cardiovascular health: data from the Baltimore Longitudinal Study of Aging. PLoS One. 2010;5:e10099.PubMedPubMedCentral
27.
go back to reference Lommatzsch M, Zingler D, Schuhbaeck K, et al. The impact of age, weight and gender on BDNF levels in human platelets and plasma. Neurobiol Aging. 2005;26:115–23.PubMed Lommatzsch M, Zingler D, Schuhbaeck K, et al. The impact of age, weight and gender on BDNF levels in human platelets and plasma. Neurobiol Aging. 2005;26:115–23.PubMed
28.
go back to reference Zhou Z, Lu T, Xu G, Yue X, et al. Decreased serum brain-derived neurotrophic factor (BDNF) is associated with post-stroke depression but not with BDNF gene Val66Met polymorphism. Clin Chem Lab Med. 2011;49:185–9.PubMed Zhou Z, Lu T, Xu G, Yue X, et al. Decreased serum brain-derived neurotrophic factor (BDNF) is associated with post-stroke depression but not with BDNF gene Val66Met polymorphism. Clin Chem Lab Med. 2011;49:185–9.PubMed
29.
go back to reference Sun Y, Jin K, Xie L, et al. VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest. 2003;111:1843–51.PubMedPubMedCentral Sun Y, Jin K, Xie L, et al. VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest. 2003;111:1843–51.PubMedPubMedCentral
30.
go back to reference Greenberg DA, Jin K. From angiogenesis to neuropathology. Nature. 2005;438:954–9.PubMed Greenberg DA, Jin K. From angiogenesis to neuropathology. Nature. 2005;438:954–9.PubMed
31.
go back to reference Jean Le Blanc N, Guruswamy R, El Ali A. Vascular endothelial growth factor isoform-B stimulates neurovascular repair after ischemic stroke by promoting the function of pericytes via vascular endothelial growth factor receptor-1. Mol Neurobiol. 2018;55:3611-26. Jean Le Blanc N, Guruswamy R, El Ali A. Vascular endothelial growth factor isoform-B stimulates neurovascular repair after ischemic stroke by promoting the function of pericytes via vascular endothelial growth factor receptor-1. Mol Neurobiol. 2018;55:3611-26.
32.
go back to reference Chen CK, Hsu PY, Wang TM, Miao ZF, Lin RT, Juo SH. TRPV4 activation contributes functional recovery from ischemic stroke via angiogenesis and neurogenesis. Mol Neurobiol. 2018;55:4127-35. Chen CK, Hsu PY, Wang TM, Miao ZF, Lin RT, Juo SH. TRPV4 activation contributes functional recovery from ischemic stroke via angiogenesis and neurogenesis. Mol Neurobiol. 2018;55:4127-35.
33.
go back to reference Xue L, Chen H, Zhang T, Chen J, Geng Z, Zhao Y. Changes in serum vascular endothelial growth factor and endostatin concentrations associated with circulating endothelial progenitor cells after acute ischemic stroke. Metab Brain Dis. 2017;32:641–8.PubMed Xue L, Chen H, Zhang T, Chen J, Geng Z, Zhao Y. Changes in serum vascular endothelial growth factor and endostatin concentrations associated with circulating endothelial progenitor cells after acute ischemic stroke. Metab Brain Dis. 2017;32:641–8.PubMed
34.
go back to reference Chen L, Zhu YM, Li YN, et al. The 15-LO-1/15-HETE system promotes angiogenesis by upregulating VEGF in ischemic brains. Neurol Res. 2017;1:1–8. Chen L, Zhu YM, Li YN, et al. The 15-LO-1/15-HETE system promotes angiogenesis by upregulating VEGF in ischemic brains. Neurol Res. 2017;1:1–8.
35.
go back to reference Heissig B, Hattori K, Dias S, et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell. 2002;109:625–37.PubMedPubMedCentral Heissig B, Hattori K, Dias S, et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell. 2002;109:625–37.PubMedPubMedCentral
36.
go back to reference Schneider A, Krüger C, Steigleder T, et al. The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest. 2005;115:2083–98.PubMedPubMedCentral Schneider A, Krüger C, Steigleder T, et al. The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest. 2005;115:2083–98.PubMedPubMedCentral
37.
go back to reference Shyu WC, Lin SL, Yang HI, et al. Functional recovery of stroke rats induced by granulocyte colony-stimulating factor-stimulated stem cells. Circulation. 2004;110:1847–54.PubMed Shyu WC, Lin SL, Yang HI, et al. Functional recovery of stroke rats induced by granulocyte colony-stimulating factor-stimulated stem cells. Circulation. 2004;110:1847–54.PubMed
38.
go back to reference Kawada H, Takizawa S, Takanashi T, et al. Administration of hematopoietic cytokines in the subacute phase after cerebral infarction is effective for functional recovery facilitating proliferation of intrinsic neural stem/progenitor cells and transition of bone marrow-derived neuronal cells. Circulation. 2006;113:701–10.PubMed Kawada H, Takizawa S, Takanashi T, et al. Administration of hematopoietic cytokines in the subacute phase after cerebral infarction is effective for functional recovery facilitating proliferation of intrinsic neural stem/progenitor cells and transition of bone marrow-derived neuronal cells. Circulation. 2006;113:701–10.PubMed
39.
go back to reference Lichtenwalner RJ, Parent JM. Adult neurogenesis and the ischemic forebrain. J Cereb Blood Flow Metab. 2006;26:1–20.PubMed Lichtenwalner RJ, Parent JM. Adult neurogenesis and the ischemic forebrain. J Cereb Blood Flow Metab. 2006;26:1–20.PubMed
40.
go back to reference Alsina B, Vu T, Cohen-Cory S. Visualizing synapse formation in arborizing optic axons in vivo: dynamics and modulation by BDNF. Nat Neurosci. 2001;4:1093–101.PubMed Alsina B, Vu T, Cohen-Cory S. Visualizing synapse formation in arborizing optic axons in vivo: dynamics and modulation by BDNF. Nat Neurosci. 2001;4:1093–101.PubMed
41.
go back to reference Lessmann V, Gottmann K, Malcangio M. Neurotrophin secretion: current facts and future prospects. Prog Neurobiol. 2003;69:341–74. Lessmann V, Gottmann K, Malcangio M. Neurotrophin secretion: current facts and future prospects. Prog Neurobiol. 2003;69:341–74.
42.
go back to reference Louissaint A, Rao S, Leventhal C, Goldman SA. Coordinated interaction of neurogenesis and angiogenesis in the adult songbird brain. Neuron. 2002;34:945–60.PubMed Louissaint A, Rao S, Leventhal C, Goldman SA. Coordinated interaction of neurogenesis and angiogenesis in the adult songbird brain. Neuron. 2002;34:945–60.PubMed
43.
go back to reference Ohab JJ, Fleming S, Blesch A, Carmichael ST. A neurovascular niche for neurogenesis after stroke. J Neurosci. 2006;26:13007–16.PubMedPubMedCentral Ohab JJ, Fleming S, Blesch A, Carmichael ST. A neurovascular niche for neurogenesis after stroke. J Neurosci. 2006;26:13007–16.PubMedPubMedCentral
44.
go back to reference Cui X, Chen J, Zacharek A, Roberts C, Yang Y, Chopp M. Nitric oxide donor up-regulation of SDF1/CXCR4 and Ang1/Tie2 promotes neuroblast cell migration after stroke. J Neurosci Res. 2009;87:86–95.PubMedPubMedCentral Cui X, Chen J, Zacharek A, Roberts C, Yang Y, Chopp M. Nitric oxide donor up-regulation of SDF1/CXCR4 and Ang1/Tie2 promotes neuroblast cell migration after stroke. J Neurosci Res. 2009;87:86–95.PubMedPubMedCentral
45.
go back to reference Deng G, Qiu Z, Li D, Fang Y, Zhang S. Delayed administration of guanosine improves long-term functional recovery and enhances neurogenesis and angiogenesis in a mouse model of photothrombotic stroke. Mol Med Rep. 2017;15:3999–4004.PubMedPubMedCentral Deng G, Qiu Z, Li D, Fang Y, Zhang S. Delayed administration of guanosine improves long-term functional recovery and enhances neurogenesis and angiogenesis in a mouse model of photothrombotic stroke. Mol Med Rep. 2017;15:3999–4004.PubMedPubMedCentral
Metadata
Title
Association of High Serum Levels of Growth Factors with Good Outcome in Ischemic Stroke: a Multicenter Study
Authors
Tomás Sobrino
Manuel Rodríguez-Yáñez
Francisco Campos
Ramón Iglesias-Rey
Mónica Millán
Natalia Pérez de la Ossa
Antonio Dávalos
Raquel Delgado-Mederos
Alejandro Martínez-Domeño
Joan Martí-Fábregas
Mar Castellanos
Joaquín Serena
Aida Lago
Exuperio Díez-Tejedor
José Castillo
Publication date
01-08-2020
Publisher
Springer US
Published in
Translational Stroke Research / Issue 4/2020
Print ISSN: 1868-4483
Electronic ISSN: 1868-601X
DOI
https://doi.org/10.1007/s12975-019-00747-2

Other articles of this Issue 4/2020

Translational Stroke Research 4/2020 Go to the issue