Skip to main content
Top
Published in: BMC Neurology 1/2013

Open Access 01-12-2013 | Research article

Clinical significance of plasma VEGF value in ischemic stroke - research for biomarkers in ischemic stroke (REBIOS) study

Authors: Ryu Matsuo, Tetsuro Ago, Masahiro Kamouchi, Junya Kuroda, Takahiro Kuwashiro, Jun Hata, Hiroshi Sugimori, Kenji Fukuda, Seiji Gotoh, Noriko Makihara, Masayo Fukuhara, Hideto Awano, Tetsu Isomura, Kazuo Suzuki, Masahiro Yasaka, Yasushi Okada, Yutaka Kiyohara, Takanari Kitazono

Published in: BMC Neurology | Issue 1/2013

Login to get access

Abstract

Background

Vascular endothelial growth factor (VEGF) is a well-known molecule mediating neuronal survival and angiogenesis. However, its clinical significance in ischemic stroke is still controversial. The goal of this study was to examine the temporal profile of plasma VEGF value and its clinical significance in ischemic stroke with taking its subtypes into consideration.

Methods

We prospectively enrolled 171 patients with ischemic stroke and age- and gender-matched healthy subjects. The stroke patients were divided into 4 subtypes: atherothrombotic infarction (ATBI, n = 34), lacunar infarction (LAC, n = 45), cardioembolic infarction (CE, n = 49) and other types (OT, n = 43). Plasma VEGF values were measured as a part of multiplex immunoassay (Human MAP v1.6) and we obtained clinical information at 5 time points (days 0, 3, 7, 14 and 90) after the stroke onset.

Results

Plasma VEGF values were significantly higher in all stroke subtypes but OT than those in the controls throughout 90 days after stroke onset. There was no significant difference in the average VEGF values among ATBI, LAC, and CE. VEGF values were positively associated with neurological severity in CE patients, while a negative association was found in ATBI patients. After adjustment for possible confounding factors, plasma VEGF value was an independent predictor of poor functional outcome in CE patients.

Conclusions

Although plasma VEGF value increases immediately after the stroke onset equally in all stroke subtypes, its significance in functional outcome may be different among the stroke subtypes.
Appendix
Available only for authorised users
Literature
1.
go back to reference Fan YY, Hu WW, Dai HB, Zhang JX, Zhang LY, He P, Shen Y, Ohtsu H, Wei EQ, Chen Z: Activation of the central histaminergic system is involved in hypoxia-induced stroke tolerance in adult mice. J Cereb Blood Flow Metab. 2011, 31 (1): 305-314. 10.1038/jcbfm.2010.94.CrossRefPubMed Fan YY, Hu WW, Dai HB, Zhang JX, Zhang LY, He P, Shen Y, Ohtsu H, Wei EQ, Chen Z: Activation of the central histaminergic system is involved in hypoxia-induced stroke tolerance in adult mice. J Cereb Blood Flow Metab. 2011, 31 (1): 305-314. 10.1038/jcbfm.2010.94.CrossRefPubMed
2.
go back to reference Lees KR, Bluhmki E, Von Kummer R, Brott TG, Toni D, Grotta JC, Albers GW, Kaste M, Marler JR, Hamilton SA, Tilley BC, Davis SM, Donnan GA, Hacke W, Allen K, Mau J, Meier D, Del Zoppo G, De Silva DA, Butcher KS, Parsons MW, Barber PA, Levi C, Bladin C, Byrnes G: Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 2010, 375 (9727): 1695-1703. 10.1016/S0140-6736(10)60491-6.CrossRefPubMed Lees KR, Bluhmki E, Von Kummer R, Brott TG, Toni D, Grotta JC, Albers GW, Kaste M, Marler JR, Hamilton SA, Tilley BC, Davis SM, Donnan GA, Hacke W, Allen K, Mau J, Meier D, Del Zoppo G, De Silva DA, Butcher KS, Parsons MW, Barber PA, Levi C, Bladin C, Byrnes G: Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 2010, 375 (9727): 1695-1703. 10.1016/S0140-6736(10)60491-6.CrossRefPubMed
3.
go back to reference Storkebaum E, Lambrechts D, Carmeliet P: VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection. Bioessays. 2004, 26 (9): 943-954. 10.1002/bies.20092.CrossRefPubMed Storkebaum E, Lambrechts D, Carmeliet P: VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection. Bioessays. 2004, 26 (9): 943-954. 10.1002/bies.20092.CrossRefPubMed
4.
go back to reference Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF: Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983, 219 (4587): 983-985. 10.1126/science.6823562.CrossRefPubMed Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF: Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983, 219 (4587): 983-985. 10.1126/science.6823562.CrossRefPubMed
5.
go back to reference Carmeliet P: Angiogenesis in health and disease. Nat Med. 2003, 9 (6): 653-660. 10.1038/nm0603-653.CrossRefPubMed Carmeliet P: Angiogenesis in health and disease. Nat Med. 2003, 9 (6): 653-660. 10.1038/nm0603-653.CrossRefPubMed
6.
go back to reference Sun Y, Jin K, Xie L, Childs J, Mao XO, Logvinova A, Greenberg DA: VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest. 2003, 111 (12): 1843-1851.CrossRefPubMedPubMedCentral Sun Y, Jin K, Xie L, Childs J, Mao XO, Logvinova A, Greenberg DA: VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest. 2003, 111 (12): 1843-1851.CrossRefPubMedPubMedCentral
7.
go back to reference Lennmyr F, Ata KA, Funa K, Olsson Y, Terent 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 Neuropath Exp Neur. 1998, 57 (9): 874-882. 10.1097/00005072-199809000-00009.CrossRefPubMed Lennmyr F, Ata KA, Funa K, Olsson Y, Terent 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 Neuropath Exp Neur. 1998, 57 (9): 874-882. 10.1097/00005072-199809000-00009.CrossRefPubMed
8.
go back to reference Zhang ZG, Zhang L, Jiang Q, Zhang R, Davies K, Powers C, Bruggen N, Chopp M: VEGF enhances angiogenesis and promotes blood–brain barrier leakage in the ischemic brain. J Clin Invest. 2000, 106 (7): 829-838. 10.1172/JCI9369.CrossRefPubMedPubMedCentral Zhang ZG, Zhang L, Jiang Q, Zhang R, Davies K, Powers C, Bruggen N, Chopp M: VEGF enhances angiogenesis and promotes blood–brain barrier leakage in the ischemic brain. J Clin Invest. 2000, 106 (7): 829-838. 10.1172/JCI9369.CrossRefPubMedPubMedCentral
9.
go back to reference Zhang ZG, Zhang L, Tsang W, Soltanian-Zadeh H, Morris D, Zhang R, Goussev A, Powers C, Yeich T, Chopp M: 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): 379-392.CrossRefPubMed Zhang ZG, Zhang L, Tsang W, Soltanian-Zadeh H, Morris D, Zhang R, Goussev A, Powers C, Yeich T, Chopp M: 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): 379-392.CrossRefPubMed
10.
go back to reference Slevin M, Krupinski J, Slowik A, Kumar P, Szczudlik A, Gaffney J: Serial measurement of vascular endothelial growth factor and transforming growth factor-beta1 in serum of patients with acute ischemic stroke. Stroke J Cereb Circ. 2000, 31 (8): 1863-1870. 10.1161/01.STR.31.8.1863.CrossRef Slevin M, Krupinski J, Slowik A, Kumar P, Szczudlik A, Gaffney J: Serial measurement of vascular endothelial growth factor and transforming growth factor-beta1 in serum of patients with acute ischemic stroke. Stroke J Cereb Circ. 2000, 31 (8): 1863-1870. 10.1161/01.STR.31.8.1863.CrossRef
11.
go back to reference Lee SC, Lee KY, Kim YJ, Kim SH, Koh SH, Lee YJ: Serum VEGF levels in acute ischaemic strokes are correlated with long-term prognosis. Eur J Neurol. 2010, 17 (1): 45-51. 10.1111/j.1468-1331.2009.02731.x.CrossRefPubMed Lee SC, Lee KY, Kim YJ, Kim SH, Koh SH, Lee YJ: Serum VEGF levels in acute ischaemic strokes are correlated with long-term prognosis. Eur J Neurol. 2010, 17 (1): 45-51. 10.1111/j.1468-1331.2009.02731.x.CrossRefPubMed
12.
go back to reference Kamouchi M, Ueda K, Ago T, Nitta H, Kitazono T: Relationship between asian dust and ischemic stroke: a time-stratified case-crossover study. Stroke J Cereb Circ. 2012, 43 (11): 3085-3087. 10.1161/STROKEAHA.112.672501.CrossRef Kamouchi M, Ueda K, Ago T, Nitta H, Kitazono T: Relationship between asian dust and ischemic stroke: a time-stratified case-crossover study. Stroke J Cereb Circ. 2012, 43 (11): 3085-3087. 10.1161/STROKEAHA.112.672501.CrossRef
13.
go back to reference Kumai Y, Kamouchi M, Hata J, Ago T, Kitayama J, Nakane H, Sugimori H, Kitazono T: Proteinuria and clinical outcomes after ischemic stroke. Neurology. 2012, 78 (24): 1909-1915. 10.1212/WNL.0b013e318259e110.CrossRefPubMed Kumai Y, Kamouchi M, Hata J, Ago T, Kitayama J, Nakane H, Sugimori H, Kitazono T: Proteinuria and clinical outcomes after ischemic stroke. Neurology. 2012, 78 (24): 1909-1915. 10.1212/WNL.0b013e318259e110.CrossRefPubMed
14.
go back to reference Kiyohara Y, Kubo M, Kato I, Tanizaki Y, Tanaka K, Okubo K, Nakamura H, Iida M: Ten-year prognosis of stroke and risk factors for death in a Japanese community: the Hisayama study. Stroke J Cereb Circ. 2003, 34 (10): 2343-2347. 10.1161/01.STR.0000091845.14833.43.CrossRef Kiyohara Y, Kubo M, Kato I, Tanizaki Y, Tanaka K, Okubo K, Nakamura H, Iida M: Ten-year prognosis of stroke and risk factors for death in a Japanese community: the Hisayama study. Stroke J Cereb Circ. 2003, 34 (10): 2343-2347. 10.1161/01.STR.0000091845.14833.43.CrossRef
15.
go back to reference Kubo M, Hata J, Ninomiya T, Matsuda K, Yonemoto K, Nakano T, Matsushita T, Yamazaki K, Ohnishi Y, Saito S, Kitazono T, Ibayashi S, Sueishi K, Iida M, Nakamura Y, Kiyohara Y: A nonsynonymous SNP in PRKCH (protein kinase C eta) increases the risk of cerebral infarction. Nat Genet. 2007, 39 (2): 212-217. 10.1038/ng1945.CrossRefPubMed Kubo M, Hata J, Ninomiya T, Matsuda K, Yonemoto K, Nakano T, Matsushita T, Yamazaki K, Ohnishi Y, Saito S, Kitazono T, Ibayashi S, Sueishi K, Iida M, Nakamura Y, Kiyohara Y: A nonsynonymous SNP in PRKCH (protein kinase C eta) increases the risk of cerebral infarction. Nat Genet. 2007, 39 (2): 212-217. 10.1038/ng1945.CrossRefPubMed
16.
go back to reference Adams HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE: 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 J Cereb Circ. 1993, 24 (1): 35-41. 10.1161/01.STR.24.1.35.CrossRef Adams HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE: 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 J Cereb Circ. 1993, 24 (1): 35-41. 10.1161/01.STR.24.1.35.CrossRef
17.
go back to reference Graves SF, Kobayashi SD, Braughton KR, Whitney AR, Sturdevant DE, Rasmussen DL, Kirpotina LN, Quinn MT, DeLeo FR: Sublytic concentrations of Staphylococcus aureus Panton-Valentine leukocidin alter human PMN gene expression and enhance bactericidal capacity. J Leukoc Biol. 2012, 92 (2): 361-374. 10.1189/jlb.1111575.CrossRefPubMedPubMedCentral Graves SF, Kobayashi SD, Braughton KR, Whitney AR, Sturdevant DE, Rasmussen DL, Kirpotina LN, Quinn MT, DeLeo FR: Sublytic concentrations of Staphylococcus aureus Panton-Valentine leukocidin alter human PMN gene expression and enhance bactericidal capacity. J Leukoc Biol. 2012, 92 (2): 361-374. 10.1189/jlb.1111575.CrossRefPubMedPubMedCentral
18.
go back to reference Alberti KG, Zimmet PZ: Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med. 1998, 15 (7): 539-553. 10.1002/(SICI)1096-9136(199807)15:7<539::AID-DIA668>3.0.CO;2-S.CrossRefPubMed Alberti KG, Zimmet PZ: Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med. 1998, 15 (7): 539-553. 10.1002/(SICI)1096-9136(199807)15:7<539::AID-DIA668>3.0.CO;2-S.CrossRefPubMed
19.
go back to reference Zacharek A, Chen J, Cui X, Li A, Li Y, Roberts C, Feng Y, Gao Q, Chopp M: Angiopoietin1/Tie2 and VEGF/Flk1 induced by MSC treatment amplifies angiogenesis and vascular stabilization after stroke. J Cereb Blood Flow Metab. 2007, 27 (10): 1684-1691. 10.1038/sj.jcbfm.9600475.CrossRefPubMedPubMedCentral Zacharek A, Chen J, Cui X, Li A, Li Y, Roberts C, Feng Y, Gao Q, Chopp M: Angiopoietin1/Tie2 and VEGF/Flk1 induced by MSC treatment amplifies angiogenesis and vascular stabilization after stroke. J Cereb Blood Flow Metab. 2007, 27 (10): 1684-1691. 10.1038/sj.jcbfm.9600475.CrossRefPubMedPubMedCentral
20.
go back to reference Xi L, Ghosh S, Wang X, Das A, Anderson FP, Kukreja RC: Hypercholesterolemia enhances tolerance to lethal systemic hypoxia in middle-aged mice: possible role of VEGF downregulation in brain. Mol Cell Biochem. 2006, 291 (1–2): 205-211.CrossRefPubMed Xi L, Ghosh S, Wang X, Das A, Anderson FP, Kukreja RC: Hypercholesterolemia enhances tolerance to lethal systemic hypoxia in middle-aged mice: possible role of VEGF downregulation in brain. Mol Cell Biochem. 2006, 291 (1–2): 205-211.CrossRefPubMed
21.
go back to reference Marti HJ, Bernaudin M, Bellail A, Schoch H, Euler M, Petit E, Risau W: Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia. Am J Pathol. 2000, 156 (3): 965-976. 10.1016/S0002-9440(10)64964-4.CrossRefPubMedPubMedCentral Marti HJ, Bernaudin M, Bellail A, Schoch H, Euler M, Petit E, Risau W: Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia. Am J Pathol. 2000, 156 (3): 965-976. 10.1016/S0002-9440(10)64964-4.CrossRefPubMedPubMedCentral
22.
go back to reference Zhang Z, Chopp M: Vascular endothelial growth factor and angiopoietins in focal cerebral ischemia. Trends Cardiovasc Med. 2002, 12 (2): 62-66. 10.1016/S1050-1738(01)00149-9.CrossRefPubMed Zhang Z, Chopp M: Vascular endothelial growth factor and angiopoietins in focal cerebral ischemia. Trends Cardiovasc Med. 2002, 12 (2): 62-66. 10.1016/S1050-1738(01)00149-9.CrossRefPubMed
Metadata
Title
Clinical significance of plasma VEGF value in ischemic stroke - research for biomarkers in ischemic stroke (REBIOS) study
Authors
Ryu Matsuo
Tetsuro Ago
Masahiro Kamouchi
Junya Kuroda
Takahiro Kuwashiro
Jun Hata
Hiroshi Sugimori
Kenji Fukuda
Seiji Gotoh
Noriko Makihara
Masayo Fukuhara
Hideto Awano
Tetsu Isomura
Kazuo Suzuki
Masahiro Yasaka
Yasushi Okada
Yutaka Kiyohara
Takanari Kitazono
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Neurology / Issue 1/2013
Electronic ISSN: 1471-2377
DOI
https://doi.org/10.1186/1471-2377-13-32

Other articles of this Issue 1/2013

BMC Neurology 1/2013 Go to the issue