Ischemic stroke is a leading cause of disability, and current treatments to improve recovery are limited. Part of the natural recovery process after brain injury is angiogenesis. The formation of new blood vessels around the infarct appears to be important for restoration of adequate perfusion to allow for healing of brain tissue. Many potential restorative treatments may affect, and be affected by, angiogenesis, so accurate quantification of this outcome is needed. We performed a systematic review of histological methods to quantify angiogenesis after cerebral infarction. We found reports of the use of a variety of histological and general and immunostaining techniques in conjunction with a variety of analysis methods. We found no direct comparison studies and concluded that more research is needed to optimize the assessment of this important stroke outcome. 1. Introduction Ischemic stroke is a leading cause of disability, with few effective treatments available to improve recovery. Most ischemic stroke patients experience some degree of spontaneous recovery, but the natural processes leading to this recovery are unclear [1]. The formation of new blood vessels around the infarcted brain tissue, termed angiogenesis, appears to be important in restoring adequate perfusion to these healing areas [2]. Many aspects of angiogenesis and its contribution to stroke recovery are still unclear, and many potential restorative treatments may affect, and be affected by, angiogenesis; therefore, accurate quantification of this important tissue outcome is needed. We sought to review the available evidence for histological methods of quantification of angiogenesis after cerebral infarction. 2. Methods We searched PubMed in May 2012 with the search terms histolog* AND angiogenesis AND stroke OR cerebral infarct* and Google Scholar with the search terms histology, angiogenesis, stroke, and cerebral infarction. We included full-text articles in English published prior to May 2012 of unique experiments describing a histological method for quantification of angiogenesis after cerebral infarction. We excluded abstracts and articles citing methods found in other articles if no modifications were described. Titles, abstracts, or full articles were reviewed to determine if each search result matched our selection criteria. We also reviewed the references of the selected articles for additional matching articles. 3. Results The PubMed search returned 453 results, of which two met our selection criteria; we found one additional matching article in the references of the selected
References
[1]
L. I. Benowitz and S. T. Carmichael, “Promoting axonal rewiring to improve outcome after stroke,” Neurobiology of Disease, vol. 37, no. 2, pp. 259–266, 2010.
[2]
K. Arai, G. Jin, D. Navaratna, and E. H. Lo, “Brain angiogenesis in developmental and pathological processes: neurovascular injury and angiogenic recovery after stroke,” FEBS Journal, vol. 276, no. 17, pp. 4644–4652, 2009.
[3]
J. Krupinski, J. Kaluza, P. Kumar, S. Kumar, and J. M. Wang, “Role of angiogenesis in patients with cerebral ischemic stroke,” Stroke, vol. 25, no. 9, pp. 1794–1798, 1994.
[4]
M. Bernaudin, H. H. Marti, S. Roussel et al., “A potential role for erythropoietin in focal permanent cerebral ischemia in mice,” Journal of Cerebral Blood Flow and Metabolism, vol. 19, no. 6, pp. 643–651, 1999.
[5]
L. Wei, J. P. Erinjeri, C. M. Rovainen, and T. A. Woolsey, “Collateral growth and angiogenesis around cortical stroke,” Stroke, vol. 32, no. 9, pp. 2179–2184, 2001.
[6]
J. Chen, Z. G. Zhang, Y. Li et al., “Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats,” Circulation Research, vol. 92, no. 6, pp. 692–699, 2003.
[7]
Y. Li, Z. Lu, C. L. Keogh, S. P. Yu, and L. Wei, “Erythropoietin-induced neurovascular protection, angiogenesis, and cerebral blood flow restoration after focal ischemia in mice,” Journal of Cerebral Blood Flow and Metabolism, vol. 27, no. 5, pp. 1043–1054, 2007.
[8]
S.-J. Liao, J.-W. Lin, Z. Pei, C.-L. Liu, J.-S. Zeng, and R.-X. Huang, “Enhanced angiogenesis with dl-3n-butylphthalide treatment after focal cerebral ischemia in RHRSP,” Brain Research, vol. 1289, pp. 69–78, 2009.
[9]
X. Hu, H. Zheng, T. Yan et al., “Physical exercise induces expression of CD31 and facilitates neural function recovery in rats with focal cerebral infarction,” Neurological Research, vol. 32, no. 4, pp. 397–402, 2010.
[10]
N. Weidner, J. P. Semple, W. R. Welch, and J. Folkman, “Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma,” The New England Journal of Medicine, vol. 324, no. 1, pp. 1–8, 1991.
[11]
M. Otilia, D. Pirici, and C. Mǎrgǎritescu, “VEGF expression in human brain tissue after acute ischemic stroke,” Romanian Journal of Morphology and Embryology, vol. 52, no. 4, pp. 1283–1292, 2011.
[12]
W.-L. Li, J. L. Fraser, S. P. Yu, J. Zhu, Y.-J. Jiang, and L. Wei, “The role of VEGF/VEGFR2 signaling in peripheral stimulation-induced cerebral neurovascular regeneration after ischemic stroke in mice,” Experimental Brain Research, vol. 214, no. 4, pp. 503–513, 2011.
[13]
Y. Sun, K. Jin, L. Xie et al., “VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia,” Journal of Clinical Investigation, vol. 111, no. 12, pp. 1843–1851, 2003.
[14]
P. S. Manoonkitiwongsa, R. L. Schultz, E. F. Whitter, and P. D. Lyden, “Contraindications of VEGF-based therapeutic angiogenesis: effects on macrophage density and histology of normal and ischemic brains,” Vascular Pharmacology, vol. 44, no. 5, pp. 316–325, 2006.
[15]
M. P. Pusztaszeri, W. Seelentag, and F. T. Bosman, “Immunohistochemical expression of endothelial markers CD31, CD34, von Willebrand factor, and Fli-1 in normal human tissues,” Journal of Histochemistry and Cytochemistry, vol. 54, no. 4, pp. 385–395, 2006.
[16]
P. C. Brooks, R. A. F. Clark, and D. A. Cheresh, “Requirement of vascular integrin α(v)β3 for angiogenesis,” Science, vol. 264, no. 5158, pp. 569–571, 1994.
[17]
M. Bernaudin, A. Bellail, H. Marti, A. Yvon, D. Vivien, and I. Duchatelle, “Neurons and astrocytes express EPO mRNA: oxygen-sensing mechanisms that involve the redox-state of the brain,” Glia, vol. 30, pp. 271–278, 2000.
[18]
D. Ribatti, A. Vacca, A. M. Roccaro, E. Crivellato, and M. Presta, “Erythropoietin as an angiogenic factor,” European Journal of Clinical Investigation, vol. 33, no. 10, pp. 891–896, 2003.
