Ischemia/Angiogenesis-Related Molecules and Cells

  • Jin Hyun Kim
  • Seung-Ki Kim
  • Kyu-Chang Wang


Twenty-three fibroblast growth factors (FGFs) and four tyrosine kinase receptors (FGFRs) have been identified. FGF-1 and FGF-2 are potent stimulators of endothelial cell proliferation, migration, sprouting, and tube formation and bind to all four FGFRs [1] (Table 1). Ten isoforms have been identified in the brain. In particular, FGF-2 increases the expression of the vascular endothelial growth factor (VEGF) and proteases, and upregulates the expression of αvβ3 integrin complexes and other adhesion molecules in endothelial cells. Sections of the superficial temporal artery (STA) from patients with moyamoya disease (MMD) exhibit dense and strong FGFR signal and basic FGF immunoreactivity in endothelial cells, in cells scattered in the thickened intima, and in smooth muscle cells (SMCs) in the media [2]. It is reported that FGF-2 is also elevated (by ~tenfold) in the cerebrospinal fluid (CSF) of patients with MMD and is also increased in patients with good outcomes after surgical revascularization [3, 4]. The upregulation of FGF-2 can be interpreted as either promoting collateral vascularization or as the causative agent in progressive stenosis. FGF-4 has been demonstrated to increase the production of matrix metalloproteases 1 (MMP-1) and to decrease the levels of the tissue inhibitor of MMP-1 (TIMP-1) via the upregulation of VEGF by FGF-4.


Endothelial Cell Vascular Endothelial Growth Factor Hepatocyte Growth Factor Tube Formation Moyamoya Disease 
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.


  1. 1.
    Fan Y, Yang GY (2007) Therapeutic angiogenesis for brain ischemia: a brief review. J Neuroimmune Pharmacol 2:284–289PubMedCrossRefGoogle Scholar
  2. 2.
    Suzui H, Hoshimaru M, Takahashi JA et al (1994) Immunohistochemical reactions for fibroblast growth factor receptor in arteries of patients with moyamoya disease. Neurosurgery 35:20–24PubMedCrossRefGoogle Scholar
  3. 3.
    Yoshimoto T, Houkin K, Takahashi A et al (1996) Angiogenic factors in moyamoya disease. Stroke 27:2160–2165PubMedCrossRefGoogle Scholar
  4. 4.
    Takahashi A, Sawamura Y, Houkin K et al (1993) The cerebrospinal fluid in patients with moyamoya disease (spontaneous occlusion of the circle of Willis) contains high level of basic fibroblast growth factor. Neurosci Lett 160:214–216PubMedCrossRefGoogle Scholar
  5. 5.
    Yano A, Shingo T, Takeuchi A et al (2005) Encapsulated vascular endothelial growth factor-secreting cell grafts have neuroprotective and angiogenic effects on focal cerebral ischemia. J Neurosurg 103:104–114PubMedCrossRefGoogle Scholar
  6. 6.
    Takahashi T, Kalka C, Masuda H et al (1999) Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 5:434–438PubMedCrossRefGoogle Scholar
  7. 7.
    Rafat N, Beck GCh, Peña-Tapia PG et al (2009) Increased levels of circulating endothelial progenitor cells in patients with Moyamoya disease. Stroke 40:432–438PubMedCrossRefGoogle Scholar
  8. 8.
    Yancopoulos GD, Davis S, Gale NW et al (2000) Vascular-specific growth factors and blood vessel formation. Nature 407 (6801): 242–248PubMedCrossRefGoogle Scholar
  9. 9.
    Hellstrom M, Gerhardt H, Kalen M et al (2001) Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol 153:543–553PubMedCrossRefGoogle Scholar
  10. 10.
    Yamamoto M, Aoyagi M, Fukai N et al (1998) Differences in cellular responses to mitogens in arterial smooth muscle cells derived from patients with moyamoya disease. Stroke 29:1188–1193PubMedCrossRefGoogle Scholar
  11. 11.
    Kedar D, Baker CH, Killion JJ et al (2002) Blockade of the epidermal growth factor receptor signaling inhibits angiogenesis leading to regression of human renal cell carcinoma growing orthotopically in nude mice. Clin Cancer Res 8:3592–3600PubMedGoogle Scholar
  12. 12.
    Hojo M, Hoshimaru M, Miyamoto S et al (1998) Role of transforming growth factor-beta1 in the pathogenesis of moyamoya disease. J Neurosurg 89:623–629PubMedCrossRefGoogle Scholar
  13. 13.
    Smyth SS, Patterson C (2002) Tiny dancers: the integrin-growth factor nexus in angiogenic signaling. J Cell Biol 158:17–21PubMedCrossRefGoogle Scholar
  14. 14.
    Senger DR, Claffey KP, Benes JE et al (1997) Angiogenesis promoted by vascular endothelial growth factor: regulation through alpha1beta1 and alpha2beta1 integrins. Proc Natl Acad Sci USA 94:13612–13617PubMedCrossRefGoogle Scholar
  15. 15.
    Vestweber D (2008) VE-cadherin: the major endothelial adhesion molecule controlling cellular junctions and blood vessel formation. Arterioscler Thromb Vasc Biol 28(2):223–232PubMedCrossRefGoogle Scholar
  16. 16.
    Cao G, O'Brien CD, Zhou Z et al (2002) Involvement of human PECAM-1 in angiogenesis and in vitro endothelial cell migration. Am J Physiol Cell Physiol 282:C1181–1190PubMedGoogle Scholar
  17. 17.
    Cunningham LA, Wetzel M, Rosenberg GA (2005) Multiple roles for MMPs and TIMPs in cerebral ischemia. Glia 50:329–339PubMedCrossRefGoogle Scholar
  18. 18.
    Kang HS, Kim SK, Cho BK et al (2006) Single nucleotide polymorphisms of tissue inhibitor of metalloproteinase genes in familial moyamoya disease. Neurosurgery 58:1074–80PubMedCrossRefGoogle Scholar
  19. 19.
    Fujimura M, Watanabe M, Narisawa A et al (2009) Increased expression of serum matrix metallo-proteinase-9 in patients with moyamoya disease. Surg Neurol Jan 13 [Epub ahead of print]Google Scholar
  20. 20.
    Nanba R, Kuroda S, Ishikawa T et al (2004) Increased expression of hepatocyte growth factor in cerebrospinal fluid and intracranial artery in moyamoya disease. Stroke 35:2837–2842PubMedCrossRefGoogle Scholar
  21. 21.
    Distler JH, Hirth A, Kurowska-Stolarska M et al (2003) Angiogenic and angiostatic factors in the molecular control of angiogenesis. Q J Nucl Med 47:149–161PubMedGoogle Scholar
  22. 22.
    Suárez Y, Sessa WC (2009) MicroRNAs as novel regulators of angiogenesis. Circ Res 104:442–454PubMedCrossRefGoogle Scholar
  23. 23.
    Yoshihara T, Taguchi A, Matsuyama T et al (2008) Increase in circulating CD34-positive cells in patients with angiographic evidence of moyamoya-like vessels. J Cereb Blood Flow Metab 28:1086–1089PubMedCrossRefGoogle Scholar
  24. 24.
    Harrigan MR (2003) Angiogenic factors in the central nervous system. Neurosurgery 53:639–660PubMedCrossRefGoogle Scholar
  25. 25.
    Gerhardt H, Betsholtz C (2003) Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res 314:15–23PubMedCrossRefGoogle Scholar
  26. 26.
    Jain RK (2003) Molecular regulation of vessel maturation. Nat Med 9:685–693PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2010

Authors and Affiliations

  1. 1.Clinical Research InstituteGyeongsang National University HospitalJinjuRepublic of Korea
  2. 2.Division of Pediatric NeurosurgerySeoul National University Children's Hospital, SeoulRepublic of Korea

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