The role of angiogenesis in damage and recovery from ischemic stroke

  • Juan F. ArenillasEmail author
  • Tomás Sobrino
  • José Castillo
  • Antoni Dávalos

Opinion statement

Ischemic stroke is burdened with a high morbidity and mortality in our society. However, there are few effective and largely available therapies for this devastating disease. In additon to advancing acute reperfusion therapies, there is a need to develop treatments aimed to promote repair and regeneration of brain tissue damaged by ischemia (neurorecovery). Therapeutic angiogenesis and vasculogenesis represent novel approaches of regenerative medicine that may help in the cure of patients with acute ischemic stroke. Translation of our knowledge about these processes from the bench to bedside is still underway. Although angiogenesis (the sprouting of new blood vessels from pre-existing vascular structures) is likely to contribute to neurorepair, the finality of the angiogenic response in acute ischemic stroke has not been fully elucidated. The first therapeutic approach to angiogenesis after ischemic stroke would be the modulation of the endogenous angiogenic response. In this setting, early instauration of physical activity, statins, and peroxisome proliferator-activated receptor-γ agonists may enhance angiogenesis and neuroregeneration. Gene therapy with vascular growth factors has been successfully tested in patients affected by chronic myocardial and peripheral ischemia. Regarding brain ischemia, experiments in animal models have shown that the effect of these growth factors is critically affected by the dosage, route of delivery, and time of administration in relation to stroke onset. In addition, the optimal angiogenic substance is unknown. Finally, vectors for gene transfer should be further optimized. Therapeutic vasculogenesis consists of the administration of exogenous endothelial progenitor cells in order to enhance brain repair processes. Endothelial progenitor cells may be recruited in response to cerebral ischemia and participate in reparative vasculogenesis after acute ischemic stroke. Further research is needed to clarify their role and therapeutic applicability in human brain ischemia.


Vascular Endothelial Growth Factor Ischemic Stroke Cerebral Ischemia Hepatocyte Growth Factor Acute Ischemic Stroke 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Murray CJ, Lopez AD: Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet 1997, 349:1498–1504.PubMedCrossRefGoogle Scholar
  2. 2.
    Hurtado O, Pradillo JM, Alonso-Escolano D, et al.: Neurorepair versus neuroprotection in stroke. Cerebrovasc Dis 2006, 21(suppl 2):54–63.PubMedCrossRefGoogle Scholar
  3. 3.
    Liu XS, Zhang ZG, Zhang RL, et al.: Stroke induces gene profile changes associated with neurogenesis and angiogenesis in adult subventricular zone progenitor cells. J Cereb Blood Flow Metab 2006, Jul 12; [Epub ahead of print].Google Scholar
  4. 4.
    Hayashi T, Noshita N, Sugawara T, Chan PH: Temporal profile of angiogenesis and expression of related genes in the brain after ischemia. J Cereb Blood Flow Metab 2003, 23:166–180.PubMedCrossRefGoogle Scholar
  5. 5.
    Krupinski J, Kaluza J, Kumar P, et al.: Role of angiogenesis in patients with cerebral ischemic stroke. Stroke 1994, 25:1794–1798.PubMedGoogle Scholar
  6. 6.
    Manoonkitiwongsa PS, Jackson-Friedman C, McMillan PJ, et al.: Angiogenesis after stroke is correlated with increased numbers of macrophages: the clean-up hypothesis. J Cereb Blood Flow Metab 2001, 21:1223–1231.PubMedCrossRefGoogle Scholar
  7. 7.
    Arenillas JF, Alvarez-Sabin J, Montaner J, et al.: Angiogenesis in symptom atic intracranial atherosclerosis: predominance of the inhibitor endostatin is related to a greater extent and risk of recurrence. Stroke 2005, 36:92–97.PubMedCrossRefGoogle Scholar
  8. 8.
    Asahara T, Masuda H, Takahashi T, et al.: Bone marrow origin of endothelial progenitor cells responsible for post-natal vasculogenesis in physiological and pathological neovascularization. Circ Res 1999, 85:221–228.PubMedGoogle Scholar
  9. 9.
    Hill JM, Zalos G, Halcox JP, et al.: Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003, 348:593–600.PubMedCrossRefGoogle Scholar
  10. 10.
    Zhang ZG, Zhang L, Jiang Q, Chopp M: Bone marrow-derived endothelial progenitor cells participate in cerebral neovascularization after focal cerebral ischemia in the adult mouse. Circ Res 2002, 90:284–288.PubMedCrossRefGoogle Scholar
  11. 11.
    Ghani U, Shuaib A, Salam A, et al.: Endothelial progenitor cells during cerebrovascular disease. Stroke 2005, 36:151–153.PubMedCrossRefGoogle Scholar
  12. 12.
    Sobrino T, Arenillas JF, Brea D, et al.: Relationship between endothelial progenitor cells (EPCs) and outcome in ischemic stroke [abstract]. Cerebrovasc Dis 2006, 21(suppl 4):98.Google Scholar
  13. 13.
    Hacke W, Kaste M, Bogousslavsky J, et al.: European Stroke Initiative Recommendations for Stroke Management-update 2003. Cerebrovasc Dis 2003, 16:311–337.CrossRefGoogle Scholar
  14. 14.
    Stroke Unit Trialists’ Collaboration: Organised inpatient (stroke unit) care for stroke. Cochrane Database Syst Rev 2002, 1:CD000197.Google Scholar
  15. 15.
    Endres M, Gertz K, Lindauer U, et al.: Mechanisms of stroke protection by physical activity. Ann Neurol 2003, 54:582–590.PubMedCrossRefGoogle Scholar
  16. 16.
    Laufs U, Werner N, Link A, et al.: Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis. Circulation 2004, 109:220–226.PubMedCrossRefGoogle Scholar
  17. 17.
    Gertz K, Priller J, Kronenberg G, et al.: Physical activity improves long-term stroke outcome via endothelial nitric oxide synthase-dependent augmentation of neovascularization and cerebral blood flow. Circ Res 2006, 99:1132–1140.PubMedCrossRefGoogle Scholar
  18. 18.
    Deplanque D, Masse I, Lefebvre C, et al.: Prior TIA, lipid-lowering drug use, and physical activity decrease ischemic stroke severity. Neurology 2006, 67:1403–1410.PubMedCrossRefGoogle Scholar
  19. 19.
    Madeddu P: Therapeutic angiogenesis and vasculogenesis for tissue regeneration. Exp Physiol 2005, 90:315–326.PubMedCrossRefGoogle Scholar
  20. 20.
    Endres M: Statins and stroke. J Cereb Blood Flow Metab 2005, 25:1093–1110.PubMedCrossRefGoogle Scholar
  21. 21.
    Chen J, Zhang ZG, Li Y, et al.: Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann Neurol 2003, 53:743–751.PubMedCrossRefGoogle Scholar
  22. 22.
    Zhang R, Wang L, Zhang L, et al.: Nitric oxide enhances angiogenesis via the synthesis of vascular endothelial growth factor and cGMP after stroke in the rat. Circ Res 2003, 92:308–313.PubMedCrossRefGoogle Scholar
  23. 23.
    Chen J, Zhang C, Jiang H, et al.: Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice. J Cereb Blood Flow Metab 2005, 25:281–290.PubMedCrossRefGoogle Scholar
  24. 24.
    Amarenco P, Bogousslavsky J, Callahan A 3rd, et al.: High-dose at orvastatin after stroke or transient ischemic attack. N Engl J Med 2006, 355:549–559.PubMedCrossRefGoogle Scholar
  25. 25.
    Montaner J: Treatment with statins in the acute phase of ischemic stroke. Expert Rev Neurother 2005, 5:211–221.PubMedCrossRefGoogle Scholar
  26. 26.
    Pistrosch F, Herbrig K, Oelschlaegel U, et al.: PPAR gammaagonist rosiglitazone increases number and migratory activity of cultured endothelial progenitor cells. Atherosclerosis 2005, 183:163–167.PubMedCrossRefGoogle Scholar
  27. 27.
    Gensch C, Clever YP, Werner C, et al.: The PPAR-gamma agonist pioglitazone increases neoangiogenesis and prevents apoptosis of endothelial progenitor cells. Atherosclerosis 2006, Jul 27; [Epub ahead of print].Google Scholar
  28. 28.
    Yki-Järvinen H: The PROactive study: some answers, many questions. Lancet 2005, 366:1241–1242.PubMedCrossRefGoogle Scholar
  29. 29.
    Henry TD, Annex BH, McKendall GR, et al.: The VIVA trial: Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis. Circulation 2003, 107:1359–1365.PubMedCrossRefGoogle Scholar
  30. 30.
    Simons M, Annex BH, Laham RJ, et al.: Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2. Double-blind, randomised, controlled clinical trial. Circulation 2002, 105:788–793.PubMedCrossRefGoogle Scholar
  31. 31.
    Lederman RJ, Mendelsohn FO, Anderson RD, et al.: Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial. Lancet 2002, 359:2053–2058.PubMedCrossRefGoogle Scholar
  32. 32.
    Grines CL, Emanueli C, Desortes E, et al.: Angiogenic Gene Therapy (AGENT) trial in patients with stable angina pectoris. Circulation 2002, 105:1291–1297.PubMedCrossRefGoogle Scholar
  33. 33.
    Makinen K, Manninen H, Hedman M, et al.: Increased vascularity detected by digital subtraction angiography after VEGF gene transfer to human lower limb artery: a randomised, placebo-controlled, double blinded phase II study. Mol Ther. 2002; 6:127–133.PubMedCrossRefGoogle Scholar
  34. 34.
    Wang Y, Galvan V, Gorostiza O, et al.: Vascular endothelial growth factor improves recovery of sensorimotor and cognitive deficits after focal cerebral ischemia in the rat. Brain Res 2006, 1115:186–193.PubMedCrossRefGoogle Scholar
  35. 35.
    Bellomo M, Adamo EB, Deodato B, et al.: Enhancement of expression of vascular endothelial growth factor after adenoassociated virus gene transfer is associated with improvement of brain ischemia injury in the gerbil. Pharmacol Res 2003, 48:309–317.PubMedCrossRefGoogle Scholar
  36. 36.
    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, 22:379–392.PubMedCrossRefGoogle Scholar
  37. 37.
    Abumiya T, Yokota C, Kuge Y, Minematsu K: Aggravation of hemorrhagic transformation by early intra-arterial infusion of low-dose vascular endothelial growth factor after transient focal cerebral ischemia in rats. Brain Res 2005, 1049:95–103.PubMedCrossRefGoogle Scholar
  38. 38.
    Manoonkitiwongsa PS, Schultz RL, Whitter EF, Lyden PD: Contraindications of VEGF-based therapeutic angiogenesis: effects on macrophage density and histology of normal and ischemic brains. Vascul Pharmacol 2006, 44:316–325.PubMedCrossRefGoogle Scholar
  39. 39.
    Weis SM, Cheresh DA: Pathophysiological consequences of VEGF-induced vascular permeability. Nature 2005, 437:497–504.PubMedCrossRefGoogle Scholar
  40. 40.
    Kimura R, Nakase H, Tamaki R, Sakaki T: Vascular endothelial growth factor antagonist reduces brain edema formation and venous infarction. Stroke 2005, 36:1259–1263.PubMedCrossRefGoogle Scholar
  41. 41.
    Kaya D, Gursoy-Ozdemir Y, Yemisci M, et al.: VEGF protects brain against focal ischemia without increasing blood-brain permeability when administered intra-cerebroventricularly. J Cereb Blood Flow Metab 2005, 25:1111–1118.PubMedCrossRefGoogle Scholar
  42. 42.
    Shimamura M, Sato N, Oshima K, et al.: Novel therapeutic strategy to treat brain ischemia: overexpression of hepatocyte growth factor gene reduced ischemic injury without cerebral edem a in rat model. Circulation 2004, 109:424–431.PubMedCrossRefGoogle Scholar
  43. 43.
    Shyu WC, Lin SZ, Chiang MF, et al.: Intracerebral peripheral blood stem cell (CD34+) implantation induces neuroplasticity by enhancing beta1 integrin-mediated angiogenesis in chronic stroke rats. J Neurosci 2006, 26:3444–3453.PubMedCrossRefGoogle Scholar
  44. 44.
    Chen J, Zhang ZG, Li Y, et al.: Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circ Res 2003, 92:692–699.PubMedCrossRefGoogle Scholar
  45. 45.
    Tse HF, Thambar S, Kwong YL, et al.: Safety of catheter-based intramyocardial autologous bone marrow cells implantation for therapeutic angiogenesis. Am J Cardiol 2006, 98:60–62.PubMedCrossRefGoogle Scholar
  46. 46.
    Stamm C, Westphal B, Kleine HD, et al.: Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 2003, 361:45–46.PubMedCrossRefGoogle Scholar
  47. 47.
    Tateishi-Yuyama E, Matsubara H, Murohara T, et al.: Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet 2002, 360:427–435.PubMedCrossRefGoogle Scholar
  48. 48.
    Shyu WC, Lin SZ, Yang HI, et al.: Functional recovery of stroke rats induced by granulocyte colony-stimulating factor-stimulated stem cells. Circulation 2004, 110:1847–1854.PubMedCrossRefGoogle Scholar
  49. 49.
    Tepper OM, Galiano RD, Capla JM, et al.: Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation 2002, 106:2781–2786.PubMedCrossRefGoogle Scholar
  50. 50.
    Verma S, Kuliszewski MA, Li SH, et al.: C-reactive protein attenuates endothelial progenitor cell survival, differentiation, and function: further evidence of a mechanistic link between C-reactive protein and cardiovascular disease. Circulation 2004, 109:2058–2067.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Juan F. Arenillas
    • 1
    Email author
  • Tomás Sobrino
  • José Castillo
  • Antoni Dávalos
  1. 1.Stroke Unit, Department of NeurosciencesGermans Trias University HospitalBadalona (Barcelona)Spain

Personalised recommendations