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Angiogenesis after cerebral ischemia

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Abstract

Though the vascular system of the adult brain is extremely stable under normal baseline conditions, endothelial cells start to proliferate in response to brain ischemia. The induction of angiogenesis, primarily in the ischemic boundary zone, enhances oxygen and nutrient supply to the affected tissue. Additionally, the generation of new blood vessels facilitates highly coupled neurorestorative processes including neurogenesis and synaptogenesis which in turn lead to improved functional recovery. To take advantage of angiogenesis as a therapeutic concept for stroke treatment, the knowledge of the precise molecular mechanisms is mandatory. Especially, since a couple of growth factors involved in post-ischemic angiogenesis may have detrimental adverse effects in the brain by increasing vascular permeability. This article summarizes the knowledge of molecular mechanisms of angiogenesis following cerebral ischemia. Finally, experimental pharmacological and cellular approaches to stimulate and enhance post-ischemic angiogenesis are discussed.

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References

  1. Abramovitch R, Neeman M, Reich R et al (1998) Intercellular communication between vascular smooth muscle and endothelial cells mediated by heparin-binding epidermal growth factor-like growth factor and vascular endothelial growth factor. FEBS Lett 425:441–447. doi:10.1016/S0014-5793(98)00283-X

    PubMed  CAS  Google Scholar 

  2. Amarenco P, Bogousslavsky J, Callahan AS et al (2003) Design and baseline characteristics of the stroke prevention by aggressive reduction in cholesterol levels (SPARCL) study. Cerebrovasc Dis 16:389–395. doi:10.1159/000072562

    Article  PubMed  CAS  Google Scholar 

  3. Asahara T, Kawamoto A (2004) Endothelial progenitor cells for postnatal vasculogenesis. Am J Physiol Cell Physiol 287:C572–C579. doi:10.1152/ajpcell.00330.2003

    PubMed  CAS  Google Scholar 

  4. Asahara T, Murohara T, Sullivan A et al (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967. doi:10.1126/science.275.5302.964

    PubMed  CAS  Google Scholar 

  5. Baigent C, Keech A, Kearney PM et al (2005) Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90, 056 participants in 14 randomised trials of statins. Lancet 366:1267–1278. doi:10.1016/S0140-6736(05)67394-1

    PubMed  CAS  Google Scholar 

  6. Bao WL, Lu SD, Wang H, Sun FY (1999) Intraventricular vascular endothelial growth factor antibody increases infarct volume following transient cerebral ischemia. Zhongguo Yao Li Xue Bao 20:313–318

    PubMed  CAS  Google Scholar 

  7. Bath PM, Willmot M, Leonardi-Bee J, Bath FJ (2002) Nitric oxide donors (nitrates), l-arginine, or nitric oxide synthase inhibitors for acute stroke. Cochrane Database Syst Rev CD000398

  8. Beck H, Acker T, Puschel AW et al (2002) Cell type-specific expression of neuropilins in an MCA-occlusion model in mice suggests a potential role in post-ischemic brain remodeling. J Neuropathol Exp Neurol 61:339–350

    PubMed  CAS  Google Scholar 

  9. Beck H, Acker T, Wiessner C, Allegrini PR, Plate KH (2000) Expression of angiopoietin-1, angiopoietin-2, and tie receptors after middle cerebral artery occlusion in the rat. Am J Pathol 157:1473–1483

    PubMed  CAS  Google Scholar 

  10. Beck H, Voswinckel R, Wagner S et al (2003) Participation of bone marrow-derived cells in long-term repair processes after experimental stroke. J Cereb Blood Flow Metab 23:709–717. doi:10.1097/01.WCB.0000065940.18332.8D

    PubMed  Google Scholar 

  11. Bernaudin M, Bellail A, Marti HH et al (2000) Neurons and astrocytes express EPO mRNA: oxygen-sensing mechanisms that involve the redox-state of the brain. Glia 30:271–278. doi:10.1002/(SICI)1098-1136(200005)30:3<271::AID-GLIA6>3.0.CO;2-H

    PubMed  CAS  Google Scholar 

  12. Bernaudin M, Marti HH, Roussel S et al (1999) A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J Cereb Blood Flow Metab 19:643–651. doi:10.1097/00004647-199906000-00007

    PubMed  CAS  Google Scholar 

  13. Bogousslavsky J, Victor SJ, Salinas EO et al (2002) Fiblast (trafermin) in acute stroke: results of the European-Australian phase II/III safety and efficacy trial. Cerebrovasc Dis 14:239–251. doi:10.1159/000065683

    PubMed  CAS  Google Scholar 

  14. Carmeliet P (2000) Fibroblast growth factor-1 stimulates branching and survival of myocardial arteries: a goal for therapeutic angiogenesis? Circ Res 87:176–178

    PubMed  CAS  Google Scholar 

  15. Carmeliet P, Ferreira V, Breier G et al (1996) Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380:435–439. doi:10.1038/380435a0

    PubMed  CAS  Google Scholar 

  16. Carmeliet P, Moons L, Luttun A et al (2001) Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 7:575–583. doi:10.1038/87904

    PubMed  CAS  Google Scholar 

  17. Cheitlin MD, Hutter AM Jr, Brindis RG et al (1999) ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology/American Heart Association. J Am Coll Cardiol 33:273–282. doi:10.1016/S0735-1097(98)00656-1

    PubMed  CAS  Google Scholar 

  18. Chen H, Bagri A, Zupicich JA et al (2000) Neuropilin-2 regulates the development of selective cranial and sensory nerves and hippocampal mossy fiber projections. Neuron 25:43–56. doi:10.1016/S0896-6273(00)80870-3

    PubMed  Google Scholar 

  19. Chen HH, Chien CH, Liu HM (1994) Correlation between angiogenesis and basic fibroblast growth factor expression in experimental brain infarct. Stroke 25:1651–1657

    PubMed  CAS  Google Scholar 

  20. Chen J, Chopp M (2006) Neurorestorative treatment of stroke: cell and pharmacological approaches. NeuroRx 3:466–473. doi:10.1016/j.nurx.2006.07.007

    PubMed  CAS  Google Scholar 

  21. Chen J, Li Y, Zhang R et al (2004) Combination therapy of stroke in rats with a nitric oxide donor and human bone marrow stromal cells enhances angiogenesis and neurogenesis. Brain Res 1005:21–28. doi:10.1016/j.brainres.2003.11.080

    PubMed  CAS  Google Scholar 

  22. Chen J, Zacharek A, Zhang C et al (2005) Endothelial nitric oxide synthase regulates brain-derived neurotrophic factor expression and neurogenesis after stroke in mice. J Neurosci 25:2366–2375. doi:10.1523/JNEUROSCI.5071-04.2005

    PubMed  CAS  Google Scholar 

  23. Chen J, Zhang C, Jiang H et al (2005) Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice. J Cereb Blood Flow Metab 25:281–290. doi:10.1038/sj.jcbfm.9600034

    PubMed  Google Scholar 

  24. Chen J, Zhang ZG, Li Y et al (2003) Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann Neurol 53:743–751. doi:10.1002/ana.10555

    PubMed  CAS  Google Scholar 

  25. Cobbs CS, Chen J, Greenberg DA, Graham SH (1998) Vascular endothelial growth factor expression in transient focal cerebral ischemia in the rat. Neurosci Lett 249:79–82. doi:10.1016/S0304-3940(98)00377-2

    PubMed  CAS  Google Scholar 

  26. Dahlof B, Devereux RB, Kjeldsen SE et al (2002) Cardiovascular morbidity and mortality in the Losartan intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 359:995–1003. doi:10.1016/S0140-6736(02)08089-3

    PubMed  CAS  Google Scholar 

  27. Date I, Takagi N, Takagi K et al (2006) Hepatocyte growth factor attenuates cerebral ischemia-induced increase in permeability of the blood-brain barrier and decreases in expression of tight junctional proteins in cerebral vessels. Neurosci Lett 407:141–145. doi:10.1016/j.neulet.2006.08.050

    PubMed  CAS  Google Scholar 

  28. Demetri GD, Griffin JD (1991) Granulocyte colony-stimulating factor and its receptor. Blood 78:2791–2808

    PubMed  CAS  Google Scholar 

  29. Digicaylioglu M, Bichet S, Marti HH et al (1995) Localization of specific erythropoietin binding sites in defined areas of the mouse brain. Proc Natl Acad Sci USA 92:3717–3720. doi:10.1073/pnas.92.9.3717

    PubMed  CAS  Google Scholar 

  30. Ding G, Jiang Q, Li L et al (2008) Magnetic resonance imaging investigation of axonal remodeling and angiogenesis after embolic stroke in sildenafil-treated rats. J Cereb Blood Flow Metab 28:1440–1448. doi:10.1038/jcbfm.2008.33

    PubMed  CAS  Google Scholar 

  31. Ding S, Merkulova-Rainon T, Han ZC, Tobelem G (2003) HGF receptor up-regulation contributes to the angiogenic phenotype of human endothelial cells and promotes angiogenesis in vitro. Blood 101:4816–4822. doi:10.1182/blood-2002-06-1731

    PubMed  CAS  Google Scholar 

  32. Ding YH, Luan XD, Li J et al (2004) Exercise-induced overexpression of angiogenic factors and reduction of ischemia/reperfusion injury in stroke. Curr Neurovasc Res 1:411–420. doi:10.2174/1567202043361875

    PubMed  CAS  Google Scholar 

  33. Ehrenreich H, Hasselblatt M, Dembowski C et al (2002) Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med 8:495–505

    PubMed  CAS  Google Scholar 

  34. Fan Y, Yang GY (2007) Therapeutic angiogenesis for brain ischemia: a brief review. J Neuroimmune Pharmacol 2:284–289. doi:10.1007/s11481-007-9073-3

    PubMed  Google Scholar 

  35. Ferrara N, Carver-Moore K, Chen H et al (1996) Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380:439–442. doi:10.1038/380439a0

    PubMed  CAS  Google Scholar 

  36. Ferrario C, Abdelhamed AI, Moore M (2004) AII antagonists in hypertension, heart failure, and diabetic nephropathy: focus on losartan. Curr Med Res Opin 20:279–293. doi:10.1185/030079903125003017

    PubMed  CAS  Google Scholar 

  37. Ferrario CM (2004) The role of angiotensin antagonism in stroke prevention in patients with hypertension: focus on losartan. Curr Med Res Opin 20:1797–1804. doi:10.1185/030079904X10160

    PubMed  CAS  Google Scholar 

  38. Fong GH, Rossant J, Gertsenstein M, Breitman ML (1995) Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376:66–70. doi:10.1038/376066a0

    PubMed  CAS  Google Scholar 

  39. Forder JP, Munzenmaier DH, Greene AS (2005) Angiogenic protection from focal ischemia with angiotensin II type 1 receptor blockade in the rat. Am J Physiol Heart Circ Physiol 288:H1989–H1996. doi:10.1152/ajpheart.00839.2004

    PubMed  CAS  Google Scholar 

  40. Fuh G, Garcia KC, de Vos AM (2000) The interaction of neuropilin-1 with vascular endothelial growth factor and its receptor flt-1. J Biol Chem 275:26690–26695

    PubMed  CAS  Google Scholar 

  41. Gale NW, Thurston G, Hackett SF et al (2002) Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1. Dev Cell 3:411–423. doi:10.1016/S1534-5807(02)00217-4

    PubMed  CAS  Google Scholar 

  42. Gertz K, Priller J, Kronenberg G et al (2006) Physical activity improves long-term stroke outcome via endothelial nitric oxide synthase-dependent augmentation of neovascularization and cerebral blood flow. Circ Res 99:1132–1140. doi:10.1161/01.RES.0000250175.14861.77

    PubMed  CAS  Google Scholar 

  43. Gerwins P, Skoldenberg E, Claesson-Welsh L (2000) Function of fibroblast growth factors and vascular endothelial growth factors and their receptors in angiogenesis. Crit Rev Oncol Hematol 34:185–194. doi:10.1016/S1040-8428(00)00062-7

    PubMed  CAS  Google Scholar 

  44. Giger RJ, Cloutier JF, Sahay A et al (2000) Neuropilin-2 is required in vivo for selective axon guidance responses to secreted semaphorins. Neuron 25:29–41. doi:10.1016/S0896-6273(00)80869-7

    PubMed  CAS  Google Scholar 

  45. Gluzman-Poltorak Z, Cohen T, Herzog Y, Neufeld G (2000) Neuropilin-2 is a receptor for the vascular endothelial growth factor (VEGF) forms VEGF-145 and VEGF-165. J Biol Chem 275:18040–18045. doi:10.1074/jbc.M909259199

    PubMed  CAS  Google Scholar 

  46. Gluzman-Poltorak Z, Cohen T, Shibuya M, Neufeld G (2001) Vascular endothelial growth factor receptor-1 and neuropilin-2 form complexes. J Biol Chem 276:18688–18694. doi:10.1074/jbc.M006909200

    PubMed  CAS  Google Scholar 

  47. Goishi K, Higashiyama S, Klagsbrun M et al (1995) Phorbol ester induces the rapid processing of cell surface heparin-binding EGF-like growth factor: conversion from juxtacrine to paracrine growth factor activity. Mol Biol Cell 6:967–980

    PubMed  CAS  Google Scholar 

  48. Gunsilius E, Petzer AL, Stockhammer G, Kahler CM, Gastl G (2001) Serial measurement of vascular endothelial growth factor and transforming growth factor-beta1 in serum of patients with acute ischemic stroke. Stroke 32:275–278

    PubMed  CAS  Google Scholar 

  49. Hambrecht R, Adams V, Erbs S et al (2003) Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase. Circulation 107:3152–3158. doi:10.1161/01.CIR.0000074229.93804.5C

    PubMed  CAS  Google Scholar 

  50. Hanabusa K, Nagaya N, Iwase T et al (2005) Adrenomedullin enhances therapeutic potency of mesenchymal stem cells after experimental stroke in rats. Stroke 36:853–858. doi:10.1161/01.STR.0000157661.69482.76

    PubMed  CAS  Google Scholar 

  51. Haqqani AS, Nesic M, Preston E et al (2005) Characterization of vascular protein expression patterns in cerebral ischemia/reperfusion using laser capture microdissection and ICAT-nanoLC-MS/MS. FASEB J 19:1809–1821. doi:10.1096/fj.05-3793com

    PubMed  CAS  Google Scholar 

  52. Hara Y, Tooyama I, Yasuhara O et al (1994) Acidic fibroblast growth factor-like immunoreactivity in rat brain following cerebral infarction. Brain Res 664:101–107. doi:10.1016/0006-8993(94)91959-3

    PubMed  CAS  Google Scholar 

  53. Hashimoto T, Lam T, Boudreau NJ et al (2001) Abnormal balance in the angiopoietin-tie2 system in human brain arteriovenous malformations. Circ Res 89:111–113. doi:10.1161/hh1401.094281

    PubMed  CAS  Google Scholar 

  54. Hayashi T, Abe K, Itoyama Y (1998) Reduction of ischemic damage by application of vascular endothelial growth factor in rat brain after transient ischemia. J Cereb Blood Flow Metab 18:887–895. doi:10.1097/00004647-199808000-00009

    PubMed  CAS  Google Scholar 

  55. Hayashi T, Abe K, Sakurai M, Itoyama Y (1998) Inductions of hepatocyte growth factor and its activator in rat brain with permanent middle cerebral artery occlusion. Brain Res 799:311–316. doi:10.1016/S0006-8993(98)00391-6

    PubMed  CAS  Google Scholar 

  56. Hayashi T, Abe K, Suzuki H, Itoyama Y (1997) Rapid induction of vascular endothelial growth factor gene expression after transient middle cerebral artery occlusion in rats. Stroke 28:2039–2044

    PubMed  CAS  Google Scholar 

  57. Hayashi T, Deguchi K, Nagotani S et al (2006) Cerebral ischemia and angiogenesis. Curr Neurovasc Res 3:119–129. doi:10.2174/156720206776875902

    PubMed  CAS  Google Scholar 

  58. Hayashi T, Noshita N, Sugawara T, Chan PH (2003) Temporal profile of angiogenesis and expression of related genes in the brain after ischemia. J Cereb Blood Flow Metab 23:166–180. doi:10.1097/00004647-200302000-00004

    PubMed  CAS  Google Scholar 

  59. Hess DC, Hill WD, Martin-Studdard A et al (2002) Bone marrow as a source of endothelial cells and NeuN-expressing cells after stroke. Stroke 33:1362–1368. doi:10.1161/01.STR.0000014925.09415.C3

    PubMed  Google Scholar 

  60. Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23:1011–1027. doi:10.1200/JCO.2005.06.081

    PubMed  CAS  Google Scholar 

  61. Hiratsuka S, Minowa O, Kuno J, Noda T, Shibuya M (1998) Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci USA 95:9349–9354. doi:10.1073/pnas.95.16.9349

    PubMed  CAS  Google Scholar 

  62. Hood J, Granger HJ (1998) Protein kinase G mediates vascular endothelial growth factor-induced Raf-1 activation and proliferation in human endothelial cells. J Biol Chem 273:23504–23508. doi:10.1074/jbc.273.36.23504

    PubMed  CAS  Google Scholar 

  63. Huang Z, Huang PL, Ma J et al (1996) Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-l-arginine. J Cereb Blood Flow Metab 16:981–987. doi:10.1097/00004647-199609000-00023

    PubMed  CAS  Google Scholar 

  64. Iihara K, Hashimoto N, Tsukahara T et al (1997) Platelet-derived growth factor-BB, but not -AA, prevents delayed neuronal death after forebrain ischemia in rats. J Cereb Blood Flow Metab 17:1097–1106. doi:10.1097/00004647-199710000-00012

    PubMed  CAS  Google Scholar 

  65. Iihara K, Sasahara M, Hashimoto N, Hazama F (1996) Induction of platelet-derived growth factor beta-receptor in focal ischemia of rat brain. J Cereb Blood Flow Metab 16:941–949. doi:10.1097/00004647-199609000-00018

    PubMed  CAS  Google Scholar 

  66. Iihara K, Sasahara M, Hashimoto N et al (1994) Ischemia induces the expression of the platelet-derived growth factor-B chain in neurons and brain macrophages in vivo. J Cereb Blood Flow Metab 14:818–824

    PubMed  CAS  Google Scholar 

  67. Imamura R, Okumi M, Isaka Y et al (2008) Carbamylated erythropoietin improves angiogenesis and protects the kidneys from ischemia-reperfusion injury. Cell Transplant 17:135–141. doi:10.3727/000000008783907044

    PubMed  Google Scholar 

  68. Issa R, AlQteishat A, Mitsios N et al (2005) Expression of basic fibroblast growth factor mRNA and protein in the human brain following ischaemic stroke. Angiogenesis 8:53–62. doi:10.1007/s10456-005-5613-8

    PubMed  CAS  Google Scholar 

  69. Issa R, Krupinski J, Bujny T et al (1999) Vascular endothelial growth factor and its receptor, KDR, in human brain tissue after ischemic stroke. Lab Invest 79:417–425

    PubMed  CAS  Google Scholar 

  70. Jackson G, Keltai M, Csanady M et al (2005) Hemodynamic effects of sildenafil citrate and isosorbide mononitrate in men with coronary artery disease and erectile dysfunction. J Sex Med 2:407–414. doi:10.1111/j.1743-6109.2005.20359.x

    PubMed  CAS  Google Scholar 

  71. Jin K, Mao XO, Sun Y et al (2002) Heparin-binding epidermal growth factor-like growth factor: hypoxia-inducible expression in vitro and stimulation of neurogenesis in vitro and in vivo. J Neurosci 22:5365–5373

    PubMed  CAS  Google Scholar 

  72. Jin K, Sun Y, Xie L et al (2004) Post-ischemic administration of heparin-binding epidermal growth factor-like growth factor (HB-EGF) reduces infarct size and modifies neurogenesis after focal cerebral ischemia in the rat. J Cereb Blood Flow Metab 24:399–408. doi:10.1097/00004647-200404000-00005

    PubMed  Google Scholar 

  73. Jin K, Zhu Y, Sun Y et al (2002) Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci USA 99:11946–11950. doi:10.1073/pnas.182296499

    PubMed  CAS  Google Scholar 

  74. Jin KL, Mao XO, Greenberg DA (2000) Vascular endothelial growth factor: direct neuroprotective effect in in vitro ischemia. Proc Natl Acad Sci USA 97:10242–10247. doi:10.1073/pnas.97.18.10242

    PubMed  CAS  Google Scholar 

  75. Kataoka M, Satoh T, Manabe T et al (2004) Marked improvement with sildenafil in a patient with primary pulmonary hypertension unresponsive to epoprostenol. Intern Med 43:945–950. doi:10.2169/internalmedicine.43.945

    PubMed  Google Scholar 

  76. Kato H, Shichiri M, Marumo F, Hirata Y (1997) Adrenomedullin as an autocrine/paracrine apoptosis survival factor for rat endothelial cells. Endocrinology 138:2615–2620. doi:10.1210/en.138.6.2615

    PubMed  CAS  Google Scholar 

  77. Kawahara N, Mishima K, Higashiyama S et al (1999) The gene for heparin-binding epidermal growth factor-like growth factor is stress-inducible: its role in cerebral ischemia. J Cereb Blood Flow Metab 19:307–320. doi:10.1097/00004647-199903000-00009

    PubMed  CAS  Google Scholar 

  78. Kawamata T, Dietrich WD, Schallert T et al (1997) Intracisternal basic fibroblast growth factor enhances functional recovery and up-regulates the expression of a molecular marker of neuronal sprouting following focal cerebral infarction. Proc Natl Acad Sci USA 94:8179–8184. doi:10.1073/pnas.94.15.8179

    PubMed  CAS  Google Scholar 

  79. Kawasaki T, Kitsukawa T, Bekku Y et al (1999) A requirement for neuropilin-1 in embryonic vessel formation. Development 126:4895–4902

    PubMed  CAS  Google Scholar 

  80. Kimura R, Nakase H, Tamaki R, Sakaki T (2005) Vascular endothelial growth factor antagonist reduces brain edema formation and venous infarction. Stroke 36:1259–1263. doi:10.1161/01.STR.0000165925.20413.14

    PubMed  CAS  Google Scholar 

  81. Kitsukawa T, Shimono A, Kawakami A, Kondoh H, Fujisawa H (1995) Overexpression of a membrane protein, neuropilin, in chimeric mice causes anomalies in the cardiovascular system, nervous system and limbs. Development 121:4309–4318

    PubMed  CAS  Google Scholar 

  82. Kojda G, Cheng YC, Burchfield J, Harrison DG (2001) Dysfunctional regulation of endothelial nitric oxide synthase (eNOS) expression in response to exercise in mice lacking one eNOS gene. Circulation 103:2839–2844

    PubMed  CAS  Google Scholar 

  83. Kovacs Z, Ikezaki K, Samoto K, Inamura T, Fukui M (1996) VEGF and flt. Expression time kinetics in rat brain infarct. Stroke 27:1865–1872

    PubMed  CAS  Google Scholar 

  84. Krupinski J, Issa R, Bujny T et al (1997) A putative role for platelet-derived growth factor in angiogenesis and neuroprotection after ischemic stroke in humans. Stroke 28:564–573

    PubMed  CAS  Google Scholar 

  85. Krupinski J, Kaluza J, Kumar P, Kumar S, Wang JM (1994) Role of angiogenesis in patients with cerebral ischemic stroke. Stroke 25:1794–1798

    PubMed  CAS  Google Scholar 

  86. Krupinski J, Kumar P, Kumar S, Kaluza J (1996) Increased expression of TGF-beta 1 in brain tissue after ischemic stroke in humans. Stroke 27:852–857

    PubMed  CAS  Google Scholar 

  87. Kurozumi K, Nakamura K, Tamiya T et al (2005) Mesenchymal stem cells that produce neurotrophic factors reduce ischemic damage in the rat middle cerebral artery occlusion model. Mol Ther 11:96–104. doi:10.1016/j.ymthe.2004.09.020

    PubMed  CAS  Google Scholar 

  88. Lee HJ, Kim KS, Park IH, Kim SU (2007) Human neural stem cells over-expressing VEGF provide neuroprotection, angiogenesis and functional recovery in mouse stroke model. PLoS One 2:e156. doi:10.1371/journal.pone.0000156

    PubMed  Google Scholar 

  89. Lee MY, Ju WK, Cha JH et al (1999) Expression of vascular endothelial growth factor mRNA following transient forebrain ischemia in rats. Neurosci Lett 265:107–110. doi:10.1016/S0304-3940(99)00219-0

    PubMed  CAS  Google Scholar 

  90. Lee ST, Chu K, Jung KH et al (2005) Granulocyte colony-stimulating factor enhances angiogenesis after focal cerebral ischemia. Brain Res 1058:120–128. doi:10.1016/j.brainres.2005.07.076

    PubMed  CAS  Google Scholar 

  91. Leist M, Ghezzi P, Grasso G et al (2004) Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 305:239–242. doi:10.1126/science.1098313

    PubMed  CAS  Google Scholar 

  92. Lennmyr F, Ata KA, Funa K, Olsson Y, Terent A (1998) 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 57:874–882

    PubMed  CAS  Google Scholar 

  93. Leventhal C, Rafii S, Rafii D, Shahar A, Goldman SA (1999) Endothelial trophic support of neuronal production and recruitment from the adult mammalian subependyma. Mol Cell Neurosci 13:450–464. doi:10.1006/mcne.1999.0762

    PubMed  CAS  Google Scholar 

  94. Li F, Chong ZZ, Maiese K (2004) Erythropoietin on a tightrope: balancing neuronal and vascular protection between intrinsic and extrinsic pathways. Neurosignals 13:265–289. doi:10.1159/000081963

    PubMed  Google Scholar 

  95. Li L, Jiang Q, Zhang L et al (2007) Angiogenesis and improved cerebral blood flow in the ischemic boundary area detected by MRI after administration of sildenafil to rats with embolic stroke. Brain Res 1132:185–192. doi:10.1016/j.brainres.2006.10.098

    PubMed  CAS  Google Scholar 

  96. Li Q, Stephenson D (2002) Postischemic administration of basic fibroblast growth factor improves sensorimotor function and reduces infarct size following permanent focal cerebral ischemia in the rat. Exp Neurol 177:531–537. doi:10.1006/exnr.2002.7994

    PubMed  CAS  Google Scholar 

  97. Li Y, Chen J, Chen XG et al (2002) Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery. Neurology 59:514–523

    PubMed  CAS  Google Scholar 

  98. Li Y, Lu Z, Keogh CL, Yu SP, Wei L (2007) Erythropoietin-induced neurovascular protection, angiogenesis, and cerebral blood flow restoration after focal ischemia in mice. J Cereb Blood Flow Metab 27:1043–1054

    PubMed  CAS  Google Scholar 

  99. Li Y, Lu ZY, Ogle M, Wei L (2007) Erythropoietin prevents blood brain barrier damage induced by focal cerebral ischemia in mice. Neurochem Res 32:2132–2141. doi:10.1007/s11064-007-9387-9

    PubMed  CAS  Google Scholar 

  100. Liao JK (2005) Clinical implications for statin pleiotropy. Curr Opin Lipidol 16:624–629. doi:10.1097/01.mol.0000191913.16321.60

    PubMed  CAS  Google Scholar 

  101. Lin TN, Nian GM, Chen SF et al (2001) Induction of Tie-1 and Tie-2 receptor protein expression after cerebral ischemia-reperfusion. J Cereb Blood Flow Metab 21:690–701. doi:10.1097/00004647-200106000-00007

    PubMed  CAS  Google Scholar 

  102. Lin TN, Te J, Lee M, Sun GY, Hsu CY (1997) Induction of basic fibroblast growth factor (bFGF) expression following focal cerebral ischemia. Brain Res Mol Brain Res 49:255–265. doi:10.1016/S0169-328X(97)00152-6

    PubMed  CAS  Google Scholar 

  103. Lin TN, Wang CK, Cheung WM, Hsu CY (2000) Induction of angiopoietin and Tie receptor mRNA expression after cerebral ischemia-reperfusion. J Cereb Blood Flow Metab 20:387–395. doi:10.1097/00004647-200002000-00021

    PubMed  CAS  Google Scholar 

  104. Lindahl P, Johansson BR, Leveen P, Betsholtz C (1997) Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277:242–245. doi:10.1126/science.277.5323.242

    PubMed  CAS  Google Scholar 

  105. Liu H, Honmou O, Harada K et al (2006) Neuroprotection by PlGF gene-modified human mesenchymal stem cells after cerebral ischaemia. Brain 129:2734–2745. doi:10.1093/brain/awl207

    PubMed  CAS  Google Scholar 

  106. Maisonpierre PC, Suri C, Jones PF et al (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277:55–60. doi:10.1126/science.277.5322.55

    PubMed  CAS  Google Scholar 

  107. Majka M, Janowska-Wieczorek A, Ratajczak J et al (2001) Numerous growth factors, cytokines, and chemokines are secreted by human CD34(+) cells, myeloblasts, erythroblasts, and megakaryoblasts and regulate normal hematopoiesis in an autocrine/paracrine manner. Blood 97:3075–3085. doi:10.1182/blood.V97.10.3075

    PubMed  CAS  Google Scholar 

  108. Manson JE, Greenland P, LaCroix AZ et al (2002) Walking compared with vigorous exercise for the prevention of cardiovascular events in women. N Engl J Med 347:716–725. doi:10.1056/NEJMoa021067

    PubMed  Google Scholar 

  109. Marti HH, Risau W (1998) Systemic hypoxia changes the organ-specific distribution of vascular endothelial growth factor and its receptors. Proc Natl Acad Sci USA 95:15809–15814. doi:10.1073/pnas.95.26.15809

    PubMed  CAS  Google Scholar 

  110. Marti HH, Wenger RH, Rivas LA et al (1996) Erythropoietin gene expression in human, monkey and murine brain. Eur J Neurosci 8:666–676. doi:10.1111/j.1460-9568.1996.tb01252.x

    PubMed  CAS  Google Scholar 

  111. Marti HJ, Bernaudin M, Bellail A et al (2000) Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia. Am J Pathol 156:965–976

    PubMed  CAS  Google Scholar 

  112. Massague J (1990) The transforming growth factor-beta family. Annu Rev Cell Biol 6:597–641. doi:10.1146/annurev.cb.06.110190.003121

    PubMed  CAS  Google Scholar 

  113. Matsuzaki H, Tamatani M, Yamaguchi A et al (2001) Vascular endothelial growth factor rescues hippocampal neurons from glutamate-induced toxicity: signal transduction cascades. FASEB J 15:1218–1220

    PubMed  CAS  Google Scholar 

  114. Migdal M, Huppertz B, Tessler S et al (1998) Neuropilin-1 is a placenta growth factor-2 receptor. J Biol Chem 273:22272–22278. doi:10.1074/jbc.273.35.22272

    PubMed  CAS  Google Scholar 

  115. Miller DL, Ortega S, Bashayan O, Basch R, Basilico C (2000) Compensation by fibroblast growth factor 1 (FGF1) does not account for the mild phenotypic defects observed in FGF2 null mice. Mol Cell Biol 20:2260–2268. doi:10.1128/MCB.20.6.2260-2268.2000

    PubMed  CAS  Google Scholar 

  116. Mishima K, Higashiyama S, Nagashima Y et al (1996) Regional distribution of heparin-binding epidermal growth factor-like growth factor mRNA and protein in adult rat forebrain. Neurosci Lett 213:153–156

    PubMed  CAS  Google Scholar 

  117. Miyazawa T, Matsumoto K, Ohmichi H et al (1998) Protection of hippocampal neurons from ischemia-induced delayed neuronal death by hepatocyte growth factor: a novel neurotrophic factor. J Cereb Blood Flow Metab 18:345–348. doi:10.1097/00004647-199804000-00001

    PubMed  CAS  Google Scholar 

  118. Monacci WT, Merrill MJ, Oldfield EH (1993) Expression of vascular permeability factor/vascular endothelial growth factor in normal rat tissues. Am J Physiol 264:C995–C1002

    PubMed  CAS  Google Scholar 

  119. Munzenmaier DH, Greene AS (1996) Opposing actions of angiotensin II on microvascular growth and arterial blood pressure. Hypertension 27:760–765

    PubMed  CAS  Google Scholar 

  120. Munzenmaier DH, Greene AS (2006) Chronic angiotensin II AT1 receptor blockade increases cerebral cortical microvessel density. Am J Physiol Heart Circ Physiol 290:H512–H516. doi:10.1152/ajpheart.01136.2004

    PubMed  CAS  Google Scholar 

  121. Murasawa S, Asahara T (2005) Endothelial progenitor cells for vasculogenesis. Physiology (Bethesda) 20:36–42. doi:10.1152/physiol.00033.2004

    CAS  Google Scholar 

  122. Murohara T, Asahara T, Silver M et al (1998) Nitric oxide synthase modulates angiogenesis in response to tissue ischemia. J Clin Invest 101:2567–2578. doi:10.1172/JCI1560

    PubMed  CAS  Google Scholar 

  123. Odorisio T, Schietroma C, Zaccaria ML et al (2002) Mice overexpressing placenta growth factor exhibit increased vascularization and vessel permeability. J Cell Sci 115:2559–2567

    PubMed  CAS  Google Scholar 

  124. Onda T, Honmou O, Harada K et al (2008) Therapeutic benefits by human mesenchymal stem cells (hMSCs) and Ang-1 gene-modified hMSCs after cerebral ischemia. J Cereb Blood Flow Metab 28:329–340. doi:10.1038/sj.jcbfm.9600527

    PubMed  CAS  Google Scholar 

  125. Plate KH, Beck H, Danner S, Allegrini PR, Wiessner C (1999) Cell type specific upregulation of vascular endothelial growth factor in an MCA-occlusion model of cerebral infarct. J Neuropathol Exp Neurol 58:654–666. doi:10.1097/00005072-199906000-00010

    PubMed  CAS  Google Scholar 

  126. Puri MC, Rossant J, Alitalo K, Bernstein A, Partanen J (1995) The receptor tyrosine kinase TIE is required for integrity and survival of vascular endothelial cells. EMBO J 14:5884–5891

    PubMed  CAS  Google Scholar 

  127. Renner O, Tsimpas A, Kostin S et al (2003) Time- and cell type-specific induction of platelet-derived growth factor receptor-beta during cerebral ischemia. Brain Res Mol Brain Res 113:44–51. doi:10.1016/S0169-328X(03)00085-8

    PubMed  CAS  Google Scholar 

  128. Ribatti D, Presta M, Vacca A et al (1999) Human erythropoietin induces a pro-angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Blood 93:2627–2636

    PubMed  CAS  Google Scholar 

  129. Ribatti D, Vacca A, Roccaro AM, Crivellato E, Presta M (2003) Erythropoietin as an angiogenic factor. Eur J Clin Invest 33:891–896. doi:10.1046/j.1365-2362.2003.01245.x

    PubMed  CAS  Google Scholar 

  130. Roberts AB, Sporn MB, Assoian RK et al (1986) Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci USA 83:4167–4171. doi:10.1073/pnas.83.12.4167

    PubMed  CAS  Google Scholar 

  131. Rudic RD, Shesely EG, Maeda N et al (1998) Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling. J Clin Invest 101:731–736. doi:10.1172/JCI1699

    PubMed  CAS  Google Scholar 

  132. Sacco RL, Gan R, Boden-Albala B et al (1998) Leisure-time physical activity and ischemic stroke risk: the Northern Manhattan Stroke Study. Stroke 29:380–387

    PubMed  CAS  Google Scholar 

  133. Salom JB, Orti M, Centeno JM, Torregrosa G, Alborch E (2000) Reduction of infarct size by the NO donors sodium nitroprusside and spermine/NO after transient focal cerebral ischemia in rats. Brain Res 865:149–156. doi:10.1016/S0006-8993(00)02095-3

    PubMed  CAS  Google Scholar 

  134. Sato TN, Tozawa Y, Deutsch U et al (1995) Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 376:70–74. doi:10.1038/376070a0

    PubMed  CAS  Google Scholar 

  135. Schanzer A, Wachs FP, Wilhelm D et al (2004) Direct stimulation of adult neural stem cells in vitro and neurogenesis in vivo by vascular endothelial growth factor. Brain Pathol 14:237–248

    PubMed  Google Scholar 

  136. Shalaby F, Rossant J, Yamaguchi TP et al (1995) Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376:62–66. doi:10.1038/376062a0

    PubMed  CAS  Google Scholar 

  137. Sheth A, Park JE, Ong YE, Ho TB, Madden BP (2005) Early haemodynamic benefit of sildenafil in patients with coexisting chronic thromboembolic pulmonary hypertension and left ventricular dysfunction. Vascul Pharmacol 42:41–45. doi:10.1016/j.vph.2004.11.005

    PubMed  CAS  Google Scholar 

  138. Shimamura M, Sato N, Oshima K et al (2004) Novel therapeutic strategy to treat brain ischemia: overexpression of hepatocyte growth factor gene reduced ischemic injury without cerebral edema in rat model. Circulation 109:424–431. doi:10.1161/01.CIR.0000109496.82683.49

    PubMed  CAS  Google Scholar 

  139. Shimamura M, Sato N, Sata M et al (2007) Delayed postischemic treatment with fluvastatin improved cognitive impairment after stroke in rats. Stroke 38:3251–3258. doi:10.1161/STROKEAHA.107.485045

    PubMed  CAS  Google Scholar 

  140. Shyu WC, Lin SZ, Yang HI et al (2004) Functional recovery of stroke rats induced by granulocyte colony-stimulating factor-stimulated stem cells. Circulation 110:1847–1854. doi:10.1161/01.CIR.0000142616.07367.66

    PubMed  CAS  Google Scholar 

  141. Slevin M, Krupinski J, Slowik A et al (2000) Serial measurement of vascular endothelial growth factor and transforming growth factor-beta1 in serum of patients with acute ischemic stroke. Stroke 31:1863–1870

    PubMed  CAS  Google Scholar 

  142. Sobrino T, Hurtado O, Moro MA et al (2007) The increase of circulating endothelial progenitor cells after acute ischemic stroke is associated with good outcome. Stroke 38:2759–2764. doi:10.1161/STROKEAHA.107.484386

    PubMed  Google Scholar 

  143. Soker S, Miao HQ, Nomi M, Takashima S, Klagsbrun M (2002) VEGF165 mediates formation of complexes containing VEGFR-2 and neuropilin-1 that enhance VEGF165-receptor binding. J Cell Biochem 85:357–368. doi:10.1002/jcb.10140

    PubMed  CAS  Google Scholar 

  144. Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M (1998) Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92:735–745. doi:10.1016/S0092-8674(00)81402-6

    PubMed  CAS  Google Scholar 

  145. Stratmann A, Risau W, Plate KH (1998) Cell type-specific expression of angiopoietin-1 and angiopoietin-2 suggests a role in glioblastoma angiogenesis. Am J Pathol 153:1459–1466

    PubMed  CAS  Google Scholar 

  146. Sugiura S, Kitagawa K, Tanaka S et al (2005) Adenovirus-mediated gene transfer of heparin-binding epidermal growth factor-like growth factor enhances neurogenesis and angiogenesis after focal cerebral ischemia in rats. Stroke 36:859–864. doi:10.1161/01.STR.0000158905.22871.95

    PubMed  CAS  Google Scholar 

  147. Sun Y, Jin K, Xie L et al (2003) VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest 111:1843–1851

    PubMed  CAS  Google Scholar 

  148. Suri C, Jones PF, Patan S et al (1996) Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87:1171–1180. doi:10.1016/S0092-8674(00)81813-9

    PubMed  CAS  Google Scholar 

  149. Taguchi A, Soma T, Tanaka H et al (2004) Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model. J Clin Invest 114:330–338

    PubMed  CAS  Google Scholar 

  150. Takashima S, Kitakaze M, Asakura M et al (2002) Targeting of both mouse neuropilin-1 and neuropilin-2 genes severely impairs developmental yolk sac and embryonic angiogenesis. Proc Natl Acad Sci USA 99:3657–3662. doi:10.1073/pnas.022017899

    PubMed  CAS  Google Scholar 

  151. Tan CC, Eckardt KU, Firth JD, Ratcliffe PJ (1992) Feedback modulation of renal and hepatic erythropoietin mRNA in response to graded anemia and hypoxia. Am J Physiol 263:F474–F481

    PubMed  CAS  Google Scholar 

  152. Thurston G, Rudge JS, Ioffe E et al (2000) Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat Med 6:460–463. doi:10.1038/74725

    PubMed  CAS  Google Scholar 

  153. Tokunaga N, Nagaya N, Shirai M et al (2004) Adrenomedullin gene transfer induces therapeutic angiogenesis in a rabbit model of chronic hind limb ischemia: benefits of a novel nonviral vector, gelatin. Circulation 109:526–531. doi:10.1161/01.CIR.0000109700.81266.32

    PubMed  CAS  Google Scholar 

  154. Toth ZE, Leker RR, Shahar T et al (2008) The combination of granulocyte colony-stimulating factor and stem cell factor significantly increases the number of bone marrow-derived endothelial cells in brains of mice following cerebral ischemia. Blood 111:5544–5552. doi:10.1182/blood-2007-10-119073

    PubMed  CAS  Google Scholar 

  155. Tsuzuki N, Miyazawa T, Matsumoto K, Nakamura T, Shima K (2001) Hepatocyte growth factor reduces the infarct volume after transient focal cerebral ischemia in rats. Neurol Res 23:417–424. doi:10.1179/016164101101198659

    PubMed  CAS  Google Scholar 

  156. Tsuzuki N, Miyazawa T, Matsumoto K et al (2000) Hepatocyte growth factor reduces infarct volume after transient focal cerebral ischemia in rats. Acta Neurochir Suppl (Wien) 76:311–316

    CAS  Google Scholar 

  157. van Bruggen N, Thibodeaux H, Palmer JT et al (1999) VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. J Clin Invest 104:1613–1620. doi:10.1172/JCI8218

    PubMed  Google Scholar 

  158. Veltkamp R, Rajapakse N, Robins G et al (2002) Transient focal ischemia increases endothelial nitric oxide synthase in cerebral blood vessels. Stroke 33:2704–2710. doi:10.1161/01.STR.0000033132.85123.6A

    PubMed  CAS  Google Scholar 

  159. Villa P, van Bruggen J, Larsen AK et al (2007) Reduced functional deficits, neuroinflammation, and secondary tissue damage after treatment of stroke by nonerythropoietic erythropoietin derivatives. J Cereb Blood Flow Metab 27:552–563. doi:10.1038/sj.jcbfm.9600370

    PubMed  CAS  Google Scholar 

  160. Walter DH, Rittig K, Bahlmann FH et al (2002) Statin therapy accelerates reendothelialization: a novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells. Circulation 105:3017–3024. doi:10.1161/01.CIR.0000018166.84319.55

    PubMed  CAS  Google Scholar 

  161. Wang L, Zhang Z, Wang Y, Zhang R, Chopp M (2004) Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke 35:1732–1737. doi:10.1161/01.STR.0000132196.49028.a4

    PubMed  CAS  Google Scholar 

  162. Wang Y, Kilic E, Kilic U et al (2005) VEGF overexpression induces post-ischaemic neuroprotection, but facilitates haemodynamic steal phenomena. Brain 128:52–63. doi:10.1093/brain/awh325

    PubMed  Google Scholar 

  163. Watanabe H, Ohashi K, Takeuchi K et al (2002) Sildenafil for primary and secondary pulmonary hypertension. Clin Pharmacol Ther 71:398–402. doi:10.1067/mcp.2002.123554

    PubMed  Google Scholar 

  164. Weintraub MI (2006) Thrombolysis (tissue plasminogen activator) in stroke: a medicolegal quagmire. Stroke 37:1917–1922. doi:10.1161/01.STR.0000226651.04862.da

    PubMed  Google Scholar 

  165. Wiessner C, Gehrmann J, Lindholm D et al (1993) Expression of transforming growth factor-beta 1 and interleukin-1 beta mRNA in rat brain following transient forebrain ischemia. Acta Neuropathol 86:439–446. doi:10.1007/BF00228578

    PubMed  CAS  Google Scholar 

  166. Wislet-Gendebien S, Bruyere F, Hans G et al (2004) Nestin-positive mesenchymal stem cells favour the astroglial lineage in neural progenitors and stem cells by releasing active BMP4. BMC Neurosci 5:33. doi:10.1186/1471-2202-5-33

    PubMed  Google Scholar 

  167. Wu H, Lee SH, Gao J, Liu X, Iruela-Arispe ML (1999) Inactivation of erythropoietin leads to defects in cardiac morphogenesis. Development 126:3597–3605

    PubMed  CAS  Google Scholar 

  168. Xia CF, Yin H, Borlongan CV, Chao L, Chao J (2004) Kallikrein gene transfer protects against ischemic stroke by promoting glial cell migration and inhibiting apoptosis. Hypertension 43:452–459. doi:10.1161/01.HYP.0000110905.29389.e5

    PubMed  CAS  Google Scholar 

  169. Xia CF, Yin H, Yao YY et al (2006) Kallikrein protects against ischemic stroke by inhibiting apoptosis and inflammation and promoting angiogenesis and neurogenesis. Hum Gene Ther 17:206–219. doi:10.1089/hum.2006.17.206

    PubMed  CAS  Google Scholar 

  170. Yamashita K, Gerken U, Vogel P, Hossmann K, Wiessner C (1999) Biphasic expression of TGF-beta1 mRNA in the rat brain following permanent occlusion of the middle cerebral artery. Brain Res 836:139–145. doi:10.1016/S0006-8993(99)01626-1

    PubMed  CAS  Google Scholar 

  171. Yamashita T, Ninomiya M, Hernandez AP et al (2006) Subventricular zone-derived neuroblasts migrate and differentiate into mature neurons in the post-stroke adult striatum. J Neurosci 26:6627–6636. doi:10.1523/JNEUROSCI.0149-06.2006

    PubMed  CAS  Google Scholar 

  172. Yang EY, Moses HL (1990) Transforming growth factor beta 1-induced changes in cell migration, proliferation, and angiogenesis in the chicken chorioallantoic membrane. J Cell Biol 111:731–741. doi:10.1083/jcb.111.2.731

    PubMed  CAS  Google Scholar 

  173. Yanqing Z, Yu-Min L, Jian Q, Bao-Guo X, Chuan-Zhen L (2006) Fibronectin and neuroprotective effect of granulocyte colony-stimulating factor in focal cerebral ischemia. Brain Res 1098:161–169. doi:10.1016/j.brainres.2006.02.140

    PubMed  Google Scholar 

  174. Yao YY, Yin H, Shen B et al (2008) Tissue kallikrein promotes neovascularization and improves cardiac function by the Akt-glycogen synthase kinase-3{beta} pathway. Cardiovasc Res 80:354–364

    PubMed  CAS  Google Scholar 

  175. Yip HK, Chang LT, Chang WN et al (2008) Level and value of circulating endothelial progenitor cells in patients after acute ischemic stroke. Stroke 39:69–74. doi:10.1161/STROKEAHA.107.489401

    PubMed  Google Scholar 

  176. Zagzag D, Hooper A, Friedlander DR et al (1999) In situ expression of angiopoietins in astrocytomas identifies angiopoietin-2 as an early marker of tumor angiogenesis. Exp Neurol 159:391–400. doi:10.1006/exnr.1999.7162

    PubMed  CAS  Google Scholar 

  177. Zarnegar R (1995) Regulation of HGF and HGFR gene expression. EXS 74:33–49

    PubMed  CAS  Google Scholar 

  178. Zhang F, Iadecola C (1993) Nitroprusside improves blood flow and reduces brain damage after focal ischemia. Neuroreport 4:559–562

    Article  PubMed  CAS  Google Scholar 

  179. Zhang F, Iadecola C (1994) Reduction of focal cerebral ischemic damage by delayed treatment with nitric oxide donors. J Cereb Blood Flow Metab 14:574–580

    PubMed  CAS  Google Scholar 

  180. Zhang F, White JG, Iadecola C (1994) Nitric oxide donors increase blood flow and reduce brain damage in focal ischemia: evidence that nitric oxide is beneficial in the early stages of cerebral ischemia. J Cereb Blood Flow Metab 14:217–226

    PubMed  CAS  Google Scholar 

  181. Zhang L, Zhang RL, Wang Y et al (2005) Functional recovery in aged and young rats after embolic stroke: treatment with a phosphodiesterase type 5 inhibitor. Stroke 36:847–852. doi:10.1161/01.STR.0000158923.19956.73

    PubMed  Google Scholar 

  182. Zhang L, Zhang Z, Zhang RL et al (2006) Tadalafil, a long-acting type 5 phosphodiesterase isoenzyme inhibitor, improves neurological functional recovery in a rat model of embolic stroke. Brain Res 1118:192–198. doi:10.1016/j.brainres.2006.08.028

    PubMed  CAS  Google Scholar 

  183. Zhang R, Wang L, Zhang L et al (2003) Nitric oxide enhances angiogenesis via the synthesis of vascular endothelial growth factor and cGMP after stroke in the rat. Circ Res 92:308–313. doi:10.1161/01.RES.0000056757.93432.8C

    PubMed  CAS  Google Scholar 

  184. Zhang Z, Chopp M (2002) Vascular endothelial growth factor and angiopoietins in focal cerebral ischemia. Trends Cardiovasc Med 12:62–66. doi:10.1016/S1050-1738(01)00149-9

    PubMed  CAS  Google Scholar 

  185. Zhang ZG, Chopp M, Lu D et al (1999) Receptor tyrosine kinase tie 1 mRNA is upregulated on cerebral microvessels after embolic middle cerebral artery occlusion in rat. Brain Res 847:338–342. doi:10.1016/S0006-8993(99)02013-2

    PubMed  CAS  Google Scholar 

  186. Zhang ZG, Tsang W, Zhang L, Powers C, Chopp M (2001) Up-regulation of neuropilin-1 in neovasculature after focal cerebral ischemia in the adult rat. J Cereb Blood Flow Metab 21:541–549. doi:10.1097/00004647-200105000-00008

    PubMed  Google Scholar 

  187. Zhang ZG, Zhang L, Croll SD, Chopp M (2002) Angiopoietin-1 reduces cerebral blood vessel leakage and ischemic lesion volume after focal cerebral embolic ischemia in mice. Neuroscience 113:683–687. doi:10.1016/S0306-4522(02)00175-6

    PubMed  CAS  Google Scholar 

  188. Zhang ZG, Zhang L, Jiang Q, Chopp M (2002) Bone marrow-derived endothelial progenitor cells participate in cerebral neovascularization after focal cerebral ischemia in the adult mouse. Circ Res 90:284–288. doi:10.1161/hh0302.104460

    PubMed  CAS  Google Scholar 

  189. Zhang ZG, Zhang L, Jiang Q et al (2000) VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest 106:829–838. doi:10.1172/JCI9369

    PubMed  CAS  Google Scholar 

  190. Zhang ZG, Zhang L, Tsang W et al (2002) Correlation of VEGF and angiopoietin expression with disruption of blood-brain barrier and angiogenesis after focal cerebral ischemia. J Cereb Blood Flow Metab 22:379–392. doi:10.1097/00004647-200204000-00002

    PubMed  CAS  Google Scholar 

  191. Zhao LR, Duan WM, Reyes M et al (2002) Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats. Exp Neurol 174:11–20. doi:10.1006/exnr.2001.7853

    PubMed  Google Scholar 

  192. Zhu Y, Lee C, Shen F et al (2005) Angiopoietin-2 facilitates vascular endothelial growth factor-induced angiogenesis in the mature mouse brain. Stroke 36:1533–1537. doi:10.1161/01.STR.0000170712.46106.2e

    PubMed  CAS  Google Scholar 

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Beck, H., Plate, K.H. Angiogenesis after cerebral ischemia. Acta Neuropathol 117, 481–496 (2009). https://doi.org/10.1007/s00401-009-0483-6

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