Angiogenesis and Arteriogenesis as Stroke Targets

Part of the Springer Series in Translational Stroke Research book series (SSTSR)


Stroke is the third leading cause of morbidity and long-term disability. Reestablishment of functional microvasculature such as promotion of angiogenesis and arteriogenesis in the ischemic border creates a hospitable microenvironment for neuronal plasticity leading to functional recovery. To capitalize on angiogenesis and arteriogenesis as therapeutic targets for stroke treatment, knowledge of the precise molecular mechanisms which stimulate these vascular processes is necessary. Vascular endothelial growth factor, its receptors, the Angiopoietin-1 (Ang1)/Tie2 system and endothelial nitric oxide synthase, among other angiogenic factors mediate and contribute to post-ischemic angiogenesis and arteriogenesis. This chapter reviews molecular mechanisms which promote angiogenesis and arteriogenesis following cerebral ischemia and the associated vascular remodeling effects of experimental pharmacological (Statins and Niaspan) and cellular (bone marrow stromal cells) approaches for the treatment of stroke.


Nitric Oxide Vascular Endothelial Growth Factor Acute Ischemic Stroke Ischemic Brain Fluid Shear Stress 
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.



This work was supported by National Institute of Aging grant RO1 AG301811 (J.C) and R01-AG037506 (M.C).


  1. 1.
    Cronin CA. Intravenous tissue plasminogen activator for stroke: a review of the ECASS III results in relation to prior clinical trials. J Emerg Med. 2010;38(1):99–105.PubMedCrossRefGoogle Scholar
  2. 2.
    Carpenter CR, et al. Thrombolytic therapy for acute ischemic stroke beyond three hours. J Emerg Med. 2011;40(1):82–92.PubMedCrossRefGoogle Scholar
  3. 3.
    Katzan IL, et al. Utilization of intravenous tissue plasminogen activator for acute ischemic stroke. Arch Neurol. 2004;61(3):346–50.PubMedCrossRefGoogle Scholar
  4. 4.
    Weimar C, et al. Intravenous thrombolysis in German stroke units before and after regulatory approval of recombinant tissue plasminogen activator. Cerebrovasc Dis. 2006;22(5–6):429–31.PubMedCrossRefGoogle Scholar
  5. 5.
    Schwammenthal Y, et al. Trombolysis in acute stroke. Isr Med Assoc J. 2006;8(11):784–7.PubMedGoogle Scholar
  6. 6.
    Pratt PF, Medhora M, Harder DR. Mechanisms regulating cerebral blood flow as therapeutic targets. Curr Opin Investig Drugs. 2004;5(9):952–6.PubMedGoogle Scholar
  7. 7.
    Plate KH. Mechanisms of angiogenesis in the brain. J Neuropathol Exp Neurol. 1999;58(4):313–20.PubMedCrossRefGoogle Scholar
  8. 8.
    Renner O, et al. Time- and cell type-specific induction of platelet-derived growth factor receptor-beta during cerebral ischemia. Brain Res Mol Brain Res. 2003;113(1–2):44–51.PubMedCrossRefGoogle Scholar
  9. 9.
    Chen J, 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(6):692–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Krupinski J, et al. Role of angiogenesis in patients with cerebral ischemic stroke. Stroke. 1994;25(9):1794–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Wei L, et al. Collateral growth and angiogenesis around cortical stroke. Stroke. 2001;32(9):2179–84.PubMedCrossRefGoogle Scholar
  12. 12.
    Christoforidis GA, et al. Angiographic assessment of pial collaterals as a prognostic indicator following intra-arterial thrombolysis for acute ischemic stroke. AJNR Am J Neuroradiol. 2005;26(7):1789–97.PubMedGoogle Scholar
  13. 13.
    Liebeskind DS. Collaterals in acute stroke: beyond the clot. Neuroimaging Clin N Am. 2005;15(3):553–73, x.Google Scholar
  14. 14.
    Dor Y, Keshet E. Ischemia-driven angiogenesis. Trends Cardiovasc Med. 1997;7(8):289–94.PubMedCrossRefGoogle Scholar
  15. 15.
    Risau W. Mechanisms of angiogenesis. Nature. 1997;386(6626):671–4.PubMedCrossRefGoogle Scholar
  16. 16.
    Folkman J, D’Amore PA. Blood vessel formation: what is its molecular basis? Cell. 1996;87(7):1153–5.PubMedCrossRefGoogle Scholar
  17. 17.
    Patan S. Vasculogenesis and angiogenesis. Cancer Treat Res. 2004;117:3–32.PubMedCrossRefGoogle Scholar
  18. 18.
    Schaper W, Buschmann I. Arteriogenesis, the good and bad of it. Eur Heart J. 1999;20(18):1297–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Buschmann I, Schaper W. Arteriogenesis versus angiogenesis: two mechanisms of vessel growth. News Physiol Sci. 1999;14:121–5.PubMedGoogle Scholar
  20. 20.
    Scholz D, Cai WJ, Schaper W. Arteriogenesis, a new concept of vascular adaptation in occlusive disease. Angiogenesis. 2001;4(4):247–57.PubMedCrossRefGoogle Scholar
  21. 21.
    Buschmann I, Schaper W. The pathophysiology of the collateral circulation (arteriogenesis). J Pathol. 2000;190(3):338–42.PubMedCrossRefGoogle Scholar
  22. 22.
    van Royen N, et al. Stimulation of arteriogenesis; a new concept for the treatment of arterial occlusive disease. Cardiovasc Res. 2001;49(3):543–53.PubMedCrossRefGoogle Scholar
  23. 23.
    Seetharam D, et al. High-density lipoprotein promotes endothelial cell migration and reendothelialization via scavenger receptor-B type I. Circ Res. 2006;98(1):63–72.PubMedCrossRefGoogle Scholar
  24. 24.
    Heil M, Schaper W. Influence of mechanical, cellular, and molecular factors on collateral artery growth (arteriogenesis). Circ Res. 2004;95(5):449–58.PubMedCrossRefGoogle Scholar
  25. 25.
    Jalali S, et al. Integrin-mediated mechanotransduction requires its dynamic interaction with specific extracellular matrix (ECM) ligands. Proc Natl Acad Sci USA. 2001;98(3):1042–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Cai WJ, et al. Activation of the integrins alpha 5beta 1 and alpha v beta 3 and focal adhesion kinase (FAK) during arteriogenesis. Mol Cell Biochem. 2009;322(1–2):161–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Chen KD, et al. Mechanotransduction in response to shear stress. Roles of receptor tyrosine kinases, integrins, and Shc. J Biol Chem. 1999;274(26):18393–400.PubMedCrossRefGoogle Scholar
  28. 28.
    Chachisvilis M, Zhang YL, Frangos JA. G protein-coupled receptors sense fluid shear stress in endothelial cells. Proc Natl Acad Sci USA. 2006;103(42):15463–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Hoefer IE, et al. Arteriogenesis proceeds via ICAM-1/Mac-1- mediated mechanisms. Circ Res. 2004;94(9):1179–85.PubMedCrossRefGoogle Scholar
  30. 30.
    Behm CZ, et al. Molecular imaging of endothelial vascular cell adhesion molecule-1 expression and inflammatory cell recruitment during vasculogenesis and ischemia-mediated arteriogenesis. Circulation. 2008;117(22):2902–11.PubMedCrossRefGoogle Scholar
  31. 31.
    Hoefer IE, et al. Direct evidence for tumor necrosis factor-alpha signaling in arteriogenesis. Circulation. 2002;105(14):1639–41.PubMedCrossRefGoogle Scholar
  32. 32.
    Kosaki K, et al. Fluid shear stress increases the production of granulocyte-macrophage colony-stimulating factor by endothelial cells via mRNA stabilization. Circ Res. 1998;82(7):794–802.PubMedCrossRefGoogle Scholar
  33. 33.
    Buschmann IR, et al. GM-CSF: a strong arteriogenic factor acting by amplification of monocyte function. Atherosclerosis. 2001;159(2):343–56.PubMedCrossRefGoogle Scholar
  34. 34.
    Cai WJ, et al. Expression of endothelial nitric oxide synthase in the vascular wall during arteriogenesis. Mol Cell Biochem. 2004;264(1–2):193–200.PubMedCrossRefGoogle Scholar
  35. 35.
    Arras M, et al. Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb. J Clin Invest. 1998;101(1):40–50.PubMedCrossRefGoogle Scholar
  36. 36.
    Schaper W, Scholz D. Factors regulating arteriogenesis. Arterioscler Thromb Vasc Biol. 2003;23(7):1143–51.PubMedCrossRefGoogle Scholar
  37. 37.
    Suri C, et al. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell. 1996;87(7):1171–80.PubMedCrossRefGoogle Scholar
  38. 38.
    Pfaff D, Fiedler U, Augustin HG. Emerging roles of the Angiopoietin-Tie and the ephrin-Eph systems as regulators of cell trafficking. J Leukoc Biol. 2006;80(4):719–26.PubMedCrossRefGoogle Scholar
  39. 39.
    Marti HH, Risau W. Angiogenesis in ischemic disease. Thromb Haemost. 1999;82 Suppl 1:44–52.PubMedGoogle Scholar
  40. 40.
    Nourhaghighi N, et al. Altered expression of angiopoietins during blood–brain barrier breakdown and angiogenesis. Lab Invest. 2003;83(8):1211–22.PubMedCrossRefGoogle Scholar
  41. 41.
    Maisonpierre PC, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science. 1997;277(5322):55–60.PubMedCrossRefGoogle Scholar
  42. 42.
    Tammela T, et al. Angiopoietin-1 promotes lymphatic sprouting and hyperplasia. Blood. 2005;105(12):4642–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Mochizuki Y, et al. Angiopoietin 2 stimulates migration and tube-like structure formation of murine brain capillary endothelial cells through c-Fes and c-Fyn. J Cell Sci. 2002;115(Pt 1):175–83.PubMedGoogle Scholar
  44. 44.
    Nag S, Kapadia A, Stewart DJ. Review: molecular pathogenesis of blood–brain barrier breakdown in acute brain injury. Neuropathol Appl Neurobiol. 2011;37(1):3–23.PubMedCrossRefGoogle Scholar
  45. 45.
    Hori S, et al. A pericyte-derived angiopoietin-1 multimeric complex induces occludin gene expression in brain capillary endothelial cells through Tie-2 activation in vitro. J Neurochem. 2004;89(2):503–13.PubMedCrossRefGoogle Scholar
  46. 46.
    Iurlaro M, et al. Rat aorta-derived mural precursor cells express the Tie2 receptor and respond directly to stimulation by angiopoietins. J Cell Sci. 2003;116(Pt 17):3635–43.PubMedCrossRefGoogle Scholar
  47. 47.
    Suri C, et al. Increased vascularization in mice overexpressing angiopoietin-1. Science. 1998;282(5388):468–71.PubMedCrossRefGoogle Scholar
  48. 48.
    Zhang ZG, et al. Angiopoietin-1 reduces cerebral blood vessel leakage and ischemic lesion volume after focal cerebral embolic ischemia in mice. Neuroscience. 2002;113(3):683–7.PubMedCrossRefGoogle Scholar
  49. 49.
    Thurston G, et al. Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat Med. 2000;6(4):460–3.PubMedCrossRefGoogle Scholar
  50. 50.
    Shim WS, et al. Angiopoietin-1 promotes functional neovascularization that relieves ischemia by improving regional reperfusion in a swine chronic myocardial ischemia model. J Biomed Sci. 2006;13(4):579–91.PubMedCrossRefGoogle Scholar
  51. 51.
    Shyu KG, et al. Direct intramuscular injection of plasmid DNA encoding angiopoietin-1 but not angiopoietin-2 augments revascularization in the rabbit ischemic hindlimb. Circulation. 1998;98(19):2081–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Chae JK, et al. Coadministration of angiopoietin-1 and vascular endothelial growth factor enhances collateral vascularization. Arterioscler Thromb Vasc Biol. 2000;20(12):2573–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Siddiqui AJ, et al. Combination of angiopoietin-1 and vascular endothelial growth factor gene therapy enhances arteriogenesis in the ischemic myocardium. Biochem Biophys Res Commun. 2003;310(3):1002–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Namiecinska M, Marciniak K, Nowak JZ. VEGF as an angiogenic, neurotrophic, and neuroprotective factor. Postepy Hig Med Dosw (Online). 2005;59:573–83.Google Scholar
  55. 55.
    Ortega N, Hutchings H, Plouet J. Signal relays in the VEGF system. Front Biosci. 1999;4:D141–52.PubMedCrossRefGoogle Scholar
  56. 56.
    Zhang Z, et al. VEGF-dependent tumor angiogenesis requires inverse and reciprocal regulation of VEGFR1 and VEGFR2. Cell Death Differ. 2010;17(3):499–512.PubMedCrossRefGoogle Scholar
  57. 57.
    Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–76.PubMedCrossRefGoogle Scholar
  58. 58.
    Hess AP, et al. Expression of the vascular endothelial growth factor receptor neuropilin-1 in the human endometrium. J Reprod Immunol. 2009;79(2):129–36.PubMedCrossRefGoogle Scholar
  59. 59.
    Banerjee S, et al. VEGF-A165 induces human aortic smooth muscle cell migration by activating neuropilin-1-VEGFR1-PI3K axis. Biochemistry. 2008;47(11):3345–51.PubMedCrossRefGoogle Scholar
  60. 60.
    Zhang ZG, et al. VEGF enhances angiogenesis and promotes blood–brain barrier leakage in the ischemic brain. J Clin Invest. 2000;106(7):829–38.PubMedCrossRefGoogle Scholar
  61. 61.
    Manoonkitiwongsa PS, et al. Contraindications of VEGF-based therapeutic angiogenesis: effects on macrophage density and histology of normal and ischemic brains. Vascul Pharmacol. 2006;44(5):316–25.PubMedCrossRefGoogle Scholar
  62. 62.
    Satchell SC, Anderson KL, Mathieson PW. Angiopoietin 1 and vascular endothelial growth factor modulate human glomerular endothelial cell barrier properties. J Am Soc Nephrol. 2004;15(3):566–74.PubMedCrossRefGoogle Scholar
  63. 63.
    Valable S, et al. VEGF-induced BBB permeability is associated with an MMP-9 activity increase in cerebral ischemia: both effects decreased by Ang-1. J Cereb Blood Flow Metab. 2005;25(11):1491–504.PubMedCrossRefGoogle Scholar
  64. 64.
    Hattori K, et al. Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells. J Exp Med. 2001;193(9):1005–14.PubMedCrossRefGoogle Scholar
  65. 65.
    Gluzman Z, et al. Endothelial cells are activated by angiopoeitin-1 gene transfer and produce coordinated sprouting in vitro and arteriogenesis in vivo. Biochem Biophys Res Commun. 2007;359(2):263–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Lee PC, et al. Impaired wound healing and angiogenesis in eNOS-deficient mice. Am J Physiol. 1999;277(4 Pt 2):H1600–8.PubMedGoogle Scholar
  67. 67.
    Yu J, et al. Endothelial nitric oxide synthase is critical for ischemic remodeling, mural cell recruitment, and blood flow reserve. Proc Natl Acad Sci USA. 2005;102(31):10999–1004.PubMedCrossRefGoogle Scholar
  68. 68.
    Jozkowicz A, et al. Genetic augmentation of nitric oxide synthase increases the vascular generation of VEGF. Cardiovasc Res. 2001;51(4):773–83.PubMedCrossRefGoogle Scholar
  69. 69.
    Rudic RD, et al. Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling. J Clin Invest. 1998;101(4):731–6.PubMedCrossRefGoogle Scholar
  70. 70.
    Murohara T, et al. Nitric oxide synthase modulates angiogenesis in response to tissue ischemia. J Clin Invest. 1998;101(11):2567–78.PubMedCrossRefGoogle Scholar
  71. 71.
    Lopez-Farre A, et al. Role of nitric oxide in the control of apoptosis in the microvasculature. Int J Biochem Cell Biol. 1998;30(10):1095–106.PubMedCrossRefGoogle Scholar
  72. 72.
    Lee PC, et al. Nitric oxide induces angiogenesis and upregulates alpha(v)beta(3) integrin expression on endothelial cells. Microvasc Res. 2000;60(3):269–80.PubMedCrossRefGoogle Scholar
  73. 73.
    Dulak J, et al. Nitric oxide induces the synthesis of vascular endothelial growth factor by rat vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2000;20(3):659–66.PubMedCrossRefGoogle Scholar
  74. 74.
    Ziche M, et al. Nitric oxide promotes proliferation and plasminogen activator production by coronary venular endothelium through endogenous bFGF. Circ Res. 1997;80(6):845–52.PubMedCrossRefGoogle Scholar
  75. 75.
    Michel JB. Role of endothelial nitric oxide in the regulation of the vasomotor system. Pathol Biol (Paris). 1998;46(3):181–9.Google Scholar
  76. 76.
    Kaur S, et al. Genetic engineering with endothelial nitric oxide synthase improves functional properties of endothelial progenitor cells from patients with coronary artery disease: an in vitro study. Basic Res Cardiol. 2009;104(6):739–49.PubMedCrossRefGoogle Scholar
  77. 77.
    Yang HT, et al. Prior exercise training produces NO-dependent increases in collateral blood flow after acute arterial occlusion. Am J Physiol Heart Circ Physiol. 2002;282(1):H301–10.PubMedGoogle Scholar
  78. 78.
    Michel JB. Role of endothelial nitric oxide in the regulation of arterial tone. Rev Prat. 1997;47(20):2251–6.PubMedGoogle Scholar
  79. 79.
    Fulton D, et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature. 1999;399(6736):597–601.PubMedCrossRefGoogle Scholar
  80. 80.
    Dai X, Faber JE. Endothelial nitric oxide synthase deficiency causes collateral vessel rarefaction and impairs activation of a cell cycle gene network during arteriogenesis. Circ Res. 2010;106(12):1870–81.PubMedCrossRefGoogle Scholar
  81. 81.
    Brevetti LS, et al. Overexpression of endothelial nitric oxide synthase increases skeletal muscle blood flow and oxygenation in severe rat hind limb ischemia. J Vasc Surg. 2003;38(4):820–6.PubMedCrossRefGoogle Scholar
  82. 82.
    Prior BM, et al. Arteriogenesis: role of nitric oxide. Endothelium. 2003;10(4–5):207–16.PubMedCrossRefGoogle Scholar
  83. 83.
    Gertz K, 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(10):1132–40.PubMedCrossRefGoogle Scholar
  84. 84.
    Cramer SC, Chopp M. Recovery recapitulates ontogeny. Trends Neurosci. 2000;23(6):265–71.PubMedCrossRefGoogle Scholar
  85. 85.
    Landers M. Treatment-induced neuroplasticity following focal injury to the motor cortex. Int J Rehabil Res. 2004;27(1):1–5.PubMedCrossRefGoogle Scholar
  86. 86.
    Cairns K, Finklestein SP. Growth factors and stem cells as treatments for stroke recovery. Phys Med Rehabil Clin N Am. 2003;14(1 Suppl):S135–42.PubMedCrossRefGoogle Scholar
  87. 87.
    Hurtado O, et al. Neurorepair versus neuroprotection in stroke. Cerebrovasc Dis. 2006;21 Suppl 2:54–63.PubMedCrossRefGoogle Scholar
  88. 88.
    Jacobson TA. Overcoming ‘ageism’ bias in the treatment of hypercholesterolaemia: a review of safety issues with statins in the elderly. Drug Saf. 2006;29(5):421–48.PubMedCrossRefGoogle Scholar
  89. 89.
    Moonis M, et al. HMG-CoA reductase inhibitors improve acute ischemic stroke outcome. Stroke. 2005;36(6):1298–300.PubMedCrossRefGoogle Scholar
  90. 90.
    Skaletz-Rorowski A, Walsh K. Statin therapy and angiogenesis. Curr Opin Lipidol. 2003;14(6):599–603.PubMedCrossRefGoogle Scholar
  91. 91.
    Chen J, et al. Vascular endothelial growth factor mediates atorvastatin-induced mammalian achaete-scute homologue-1 gene expression and neuronal differentiation after stroke in retired breeder rats. Neuroscience. 2006;141(2):737–44.PubMedCrossRefGoogle Scholar
  92. 92.
    Chen J, et al. Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann Neurol. 2003;53(6):743–51.PubMedCrossRefGoogle Scholar
  93. 93.
    Sata M, et al. Statins augment collateral growth in response to ischemia but they do not promote cancer and atherosclerosis. Hypertension. 2004;43(6):1214–20.PubMedCrossRefGoogle Scholar
  94. 94.
    Skaletz-Rorowski A, et al. The pro- and antiangiogenic effects of statins. Semin Vasc Med. 2004;4(4):395–400.PubMedCrossRefGoogle Scholar
  95. 95.
    Urbich C, et al. Double-edged role of statins in angiogenesis signaling. Circ Res. 2002;90(6):737–44.PubMedCrossRefGoogle Scholar
  96. 96.
    Walter DH, et al. Statin therapy accelerates reendothelialization: a novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells. Circulation. 2002;105(25):3017–24.PubMedCrossRefGoogle Scholar
  97. 97.
    Liao JK. Clinical implications for statin pleiotropy. Curr Opin Lipidol. 2005;16(6):624–9.PubMedCrossRefGoogle Scholar
  98. 98.
    Chen J, et al. Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice. J Cereb Blood Flow Metab. 2005;25(2):281–90.PubMedCrossRefGoogle Scholar
  99. 99.
    Dimmeler S, et al. HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest. 2001;108(3):391–7.PubMedGoogle Scholar
  100. 100.
    Maeda T, Kawane T, Horiuchi N. Statins augment vascular endothelial growth factor expression in osteoblastic cells via inhibition of protein prenylation. Endocrinology. 2003;144(2):681–92.PubMedCrossRefGoogle Scholar
  101. 101.
    Walter DH, Zeiher AM, Dimmeler S. Effects of statins on endothelium and their contribution to neovascularization by mobilization of endothelial progenitor cells. Coron Artery Dis. 2004;15(5):235–42.PubMedCrossRefGoogle Scholar
  102. 102.
    Kureishi Y, et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med. 2000;6(9):1004–10.PubMedCrossRefGoogle Scholar
  103. 103.
    Khaidakov M, et al. Statins and angiogenesis: is it about connections? Biochem Biophys Res Commun. 2009;387(3):543–7.PubMedCrossRefGoogle Scholar
  104. 104.
    Zacharek A, et al. Simvastatin increases notch signaling activity and promotes arteriogenesis after stroke. Stroke. 2009;40(1):254–60.PubMedCrossRefGoogle Scholar
  105. 105.
    Lakhan SE, Bagchi S, Hofer M. Statins and clinical outcome of acute ischemic stroke: a systematic review. Int Arch Med. 2010;3:22.PubMedCrossRefGoogle Scholar
  106. 106.
    Matsumura M, et al. Effects of atorvastatin on angiogenesis in hindlimb ischemia and endothelial progenitor cell formation in rats. J Atheroscler Thromb. 2009;16(4):319–26.PubMedCrossRefGoogle Scholar
  107. 107.
    Llevadot J, et al. HMG-CoA reductase inhibitor mobilizes bone marrow—derived endothelial progenitor cells. J Clin Invest. 2001;108(3):399–405.PubMedGoogle Scholar
  108. 108.
    Dimmeler S, Dernbach E, Zeiher AM. Phosphorylation of the endothelial nitric oxide synthase at ser-1177 is required for VEGF-induced endothelial cell migration. FEBS Lett. 2000;477(3):258–62.PubMedCrossRefGoogle Scholar
  109. 109.
    Vasa M, et al. Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation. 2001;103(24):2885–90.PubMedCrossRefGoogle Scholar
  110. 110.
    Newman GC, et al. Association of diabetes, homocysteine, and HDL with cognition and disability after stroke. Neurology. 2007;69(22):2054–62.PubMedCrossRefGoogle Scholar
  111. 111.
    Sanossian N, et al. Do high-density lipoprotein cholesterol levels influence stroke severity? J Stroke Cerebrovasc Dis. 2006;15(5):187–9.PubMedCrossRefGoogle Scholar
  112. 112.
    van Exel E, et al. Association between high-density lipoprotein and cognitive impairment in the oldest old. Ann Neurol. 2002;51(6):716–21.PubMedCrossRefGoogle Scholar
  113. 113.
    Tanne D, Yaari S, Goldbourt U. High-density lipoprotein cholesterol and risk of ischemic stroke mortality. A 21-year follow-up of 8586 men from the Israeli Ischemic heart disease study. Stroke. 1997;28(1):83–7.PubMedCrossRefGoogle Scholar
  114. 114.
    Zivkovic SA, et al. Rapidly progressive stroke in a young adult with very low high-density lipoprotein cholesterol. J Neuroimaging. 2000;10(4):233–6.PubMedGoogle Scholar
  115. 115.
    Corti MC, et al. HDL cholesterol predicts coronary heart disease mortality in older persons. JAMA. 1995;274(7):539–44.PubMedCrossRefGoogle Scholar
  116. 116.
    Weverling-Rijnsburger AW, et al. High-density vs low-density lipoprotein cholesterol as the risk factor for coronary artery disease and stroke in old age. Arch Intern Med. 2003;163(13):1549–54.PubMedCrossRefGoogle Scholar
  117. 117.
    Mineo C, et al. Endothelial and antithrombotic actions of HDL. Circ Res. 2006;98(11):1352–64.PubMedCrossRefGoogle Scholar
  118. 118.
    Kuvin JT, et al. A novel mechanism for the beneficial vascular effects of high-density lipoprotein cholesterol: enhanced vasorelaxation and increased endothelial nitric oxide synthase expression. Am Heart J. 2002;144(1):165–72.PubMedCrossRefGoogle Scholar
  119. 119.
    Mineo C, et al. High density lipoprotein-induced endothelial nitric-oxide synthase activation is mediated by Akt and MAP kinases. J Biol Chem. 2003;278(11):9142–9.PubMedCrossRefGoogle Scholar
  120. 120.
    Assanasen C, et al. Cholesterol binding, efflux, and a PDZ-interacting domain of scavenger receptor-BI mediate HDL-initiated signaling. J Clin Invest. 2005;115(4):969–77.PubMedGoogle Scholar
  121. 121.
    Nofer JR, et al. HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3. J Clin Invest. 2004;113(4):569–81.PubMedGoogle Scholar
  122. 122.
    Pu DR, Liu L. HDL slowing down endothelial progenitor cells senescence: a novel anti-atherogenic property of HDL. Med Hypotheses. 2008;70(2):338–42.PubMedCrossRefGoogle Scholar
  123. 123.
    Zhang Q, et al. Essential role of HDL on endothelial progenitor cell proliferation with PI3K/Akt/cyclin D1 as the signal pathway. Exp Biol Med (Maywood). 2010;235(9):1082–92.CrossRefGoogle Scholar
  124. 124.
    Sumi M, et al. Reconstituted high-density lipoprotein stimulates differentiation of endothelial progenitor cells and enhances ischemia-induced angiogenesis. Arterioscler Thromb Vasc Biol. 2007;27(4):813–8.PubMedCrossRefGoogle Scholar
  125. 125.
    Elam MB, et al. Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT study: a randomized trial. Arterial disease multiple intervention trial. JAMA. 2000;284(10):1263–70.PubMedCrossRefGoogle Scholar
  126. 126.
    Schachter M. Strategies for modifying high-density lipoprotein cholesterol: a role for nicotinic acid. Cardiovasc Drugs Ther. 2005;19(6):415–22.PubMedCrossRefGoogle Scholar
  127. 127.
    Shepherd J, Betteridge J, Van Gaal L. Nicotinic acid in the management of dyslipidaemia associated with diabetes and metabolic syndrome: a position paper developed by a European Consensus Panel. Curr Med Res Opin. 2005;21(5):665–82.PubMedCrossRefGoogle Scholar
  128. 128.
    Kamanna VS, Kashyap ML. Mechanism of action of niacin. Am J Cardiol. 2008;101(8A):20B–6.PubMedCrossRefGoogle Scholar
  129. 129.
    Jin FY, Kamanna VS, Kashyap ML. Niacin accelerates intracellular ApoB degradation by inhibiting triacylglycerol synthesis in human hepatoblastoma (HepG2) cells. Arterioscler Thromb Vasc Biol. 1999;19(4):1051–9.PubMedCrossRefGoogle Scholar
  130. 130.
    Jin FY, Kamanna VS, Kashyap ML. Niacin decreases removal of high-density lipoprotein apolipoprotein A-I but not cholesterol ester by Hep G2 cells. Implication for reverse cholesterol transport. Arterioscler Thromb Vasc Biol. 1997;17(10):2020–8.PubMedCrossRefGoogle Scholar
  131. 131.
    Rosenson RS. Antiatherothrombotic effects of nicotinic acid. Atherosclerosis. 2003;171(1):87–96.PubMedCrossRefGoogle Scholar
  132. 132.
    Chen J, et al. Niaspan increases angiogenesis and improves functional recovery after stroke. Ann Neurol. 2007;62(1):49–58.PubMedCrossRefGoogle Scholar
  133. 133.
    Chen J, et al. Niaspan treatment increases tumor necrosis factor-alpha-converting enzyme and promotes arteriogenesis after stroke. J Cereb Blood Flow Metab. 2009;29(5):911–20.PubMedCrossRefGoogle Scholar
  134. 134.
    Chapman MJ. Therapeutic elevation of HDL-cholesterol to prevent atherosclerosis and coronary heart disease. Pharmacol Ther. 2006;111(3):893–908.PubMedCrossRefGoogle Scholar
  135. 135.
    Toth PP. High-density lipoprotein as a therapeutic target: clinical evidence and treatment strategies. Am J Cardiol. 2005;96(9A):50K–8K; discussion 34K–5K.Google Scholar
  136. 136.
    Grundmann S, et al. Anti-tumor necrosis factor-{alpha} therapies attenuate adaptive arteriogenesis in the rabbit. Am J Physiol Heart Circ Physiol. 2005;289(4):H1497–505.PubMedCrossRefGoogle Scholar
  137. 137.
    Edwards DR, Handsley MM, Pennington CJ. The ADAM metalloproteinases. Mol Aspects Med. 2008;29(5):258–89.PubMedCrossRefGoogle Scholar
  138. 138.
    Garton KJ, et al. Stimulated shedding of vascular cell adhesion molecule 1 (VCAM-1) is mediated by tumor necrosis factor-alpha-converting enzyme (ADAM 17). J Biol Chem. 2003;278(39):37459–64.PubMedCrossRefGoogle Scholar
  139. 139.
    Krause DS. Plasticity of marrow-derived stem cells. Gene Ther. 2002;9(11):754–8.PubMedCrossRefGoogle Scholar
  140. 140.
    Menasche P. Cell transplantation for the treatment of heart failure. Semin Thorac Cardiovasc Surg. 2002;14(2):157–66.PubMedCrossRefGoogle Scholar
  141. 141.
    Wang JS, et al. Marrow stromal cells for cellular cardiomyoplasty: feasibility and potential clinical advantages. J Thorac Cardiovasc Surg. 2000;120(5):999–1005.PubMedCrossRefGoogle Scholar
  142. 142.
    Chen J, et al. Therapeutic benefit of intracerebral transplantation of bone marrow stromal cells after cerebral ischemia in rats. J Neurol Sci. 2001;189(1–2):49–57.PubMedCrossRefGoogle Scholar
  143. 143.
    Li Y, et al. Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery. Neurology. 2002;59(4):514–23.PubMedCrossRefGoogle Scholar
  144. 144.
    Chen J, et al. Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke. 2001;32(4):1005–11.PubMedCrossRefGoogle Scholar
  145. 145.
    Wu J, et al. Intravenously administered bone marrow cells migrate to damaged brain tissue and improve neural function in ischemic rats. Cell Transplant. 2008;16(10):993–1005.PubMedCrossRefGoogle Scholar
  146. 146.
    Riess P, et al. Transplanted neural stem cells survive, differentiate, and improve neurological motor function after experimental traumatic brain injury. Neurosurgery. 2002;51(4):1043–52; discussion 1052–4.Google Scholar
  147. 147.
    Sanchez-Ramos J, et al. Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol. 2000;164(2):247–56.PubMedCrossRefGoogle Scholar
  148. 148.
    Tang YL, et al. Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction. Ann Thorac Surg. 2005;80(1):229–36; discussion 236–7.Google Scholar
  149. 149.
    Kinnaird T, et al. Bone marrow-derived cells for enhancing collateral development: mechanisms, animal data, and initial clinical experiences. Circ Res. 2004;95(4):354–63.PubMedCrossRefGoogle Scholar
  150. 150.
    Ponte AL, et al. The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic activities. Stem Cells. 2007;25(7):1737–45.PubMedCrossRefGoogle Scholar
  151. 151.
    Wu Y, et al. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells. 2007;25(10):2648–59.PubMedCrossRefGoogle Scholar
  152. 152.
    Kinnaird T, et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res. 2004;94(5):678–85.PubMedCrossRefGoogle Scholar
  153. 153.
    Matsuda-Hashii Y, et al. Hepatocyte growth factor plays roles in the induction and autocrine maintenance of bone marrow stromal cell IL-11, SDF-1 alpha, and stem cell factor. Exp Hematol. 2004;32(10):955–61.PubMedCrossRefGoogle Scholar
  154. 154.
    Annabi B, et al. Hypoxia promotes murine bone-marrow-derived stromal cell migration and tube formation. Stem Cells. 2003;21(3):337–47.PubMedCrossRefGoogle Scholar
  155. 155.
    Zacharek A, et al. Angiopoietin1/Tie2 and VEGF/Flk1 induced by MSC treatment amplifies angiogenesis and vascular stabilization after stroke. J Cereb Blood Flow Metab. 2007;27(10):1684–91.PubMedCrossRefGoogle Scholar
  156. 156.
    Chen J, et al. Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J Neurosci Res. 2003;73(6):778–86.PubMedCrossRefGoogle Scholar
  157. 157.
    Al-Khaldi A, et al. Postnatal bone marrow stromal cells elicit a potent VEGF-dependent neoangiogenic response in vivo. Gene Ther. 2003;10(8):621–9.PubMedCrossRefGoogle Scholar
  158. 158.
    Al-Khaldi A, et al. Therapeutic angiogenesis using autologous bone marrow stromal cells: improved blood flow in a chronic limb ischemia model. Ann Thorac Surg. 2003;75(1):204–9.PubMedCrossRefGoogle Scholar
  159. 159.
    Cui X, et al. Chemokine, vascular and therapeutic effects of combination Simvastatin and BMSC treatment of stroke. Neurobiol Dis. 2009;36(1):35–41.PubMedCrossRefGoogle Scholar
  160. 160.
    Eaves CJ, et al. Mechanisms that regulate the cell cycle status of very primitive hematopoietic cells in long-term human marrow cultures. II. Analysis of positive and negative regulators produced by stromal cells within the adherent layer. Blood. 1991;78(1):110–7.PubMedGoogle Scholar
  161. 161.
    Majumdar MK, et al. Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells. J Cell Physiol. 1998;176(1):57–66.PubMedCrossRefGoogle Scholar
  162. 162.
    Seshi B, Kumar S, Sellers D. Human bone marrow stromal cell: coexpression of markers specific for multiple mesenchymal cell lineages. Blood Cells Mol Dis. 2000;26(3):234–46.PubMedCrossRefGoogle Scholar
  163. 163.
    Bang OY, et al. Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol. 2005;57(6):874–82.PubMedCrossRefGoogle Scholar
  164. 164.
    Sykova E, et al. Bone marrow stem cells and polymer hydrogels-two strategies for spinal cord injury repair. Cell Mol Neurobiol. 2006;26(7–8):1113–29.PubMedGoogle Scholar
  165. 165.
    Malgieri A, et al. Bone marrow and umbilical cord blood human mesenchymal stem cells: state of the art. Int J Clin Exp Med. 2010;3(4):248–69.PubMedGoogle Scholar
  166. 166.
    Suarez-Monteagudo C, et al. Autologous bone marrow stem cell neurotransplantation in stroke patients. An open study. Restor Neurol Neurosci. 2009;27(3):151–61.PubMedGoogle Scholar
  167. 167.
    Lee JS, et al. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells. 2010;28(6):1099–106.PubMedCrossRefGoogle Scholar
  168. 168.
    Chen J, et al. Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke. 2001;32(11):2682–8.PubMedCrossRefGoogle Scholar
  169. 169.
    Newcomb JD, et al. Timing of cord blood treatment after experimental stroke determines therapeutic efficacy. Cell Transplant. 2006;15(3):213–23.PubMedCrossRefGoogle Scholar
  170. 170.
    Zhang L, et al. Delayed administration of human umbilical tissue-derived cells improved neurological functional recovery in a rodent model of focal ischemia. Stroke. 2011;42(5):1437–44.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of NeurologyHenry Ford HospitalDetroitUSA
  2. 2.Department of NeurologyHenry Ford HospitalDetroitUSA
  3. 3.Department of PhysicsOakland UniversityRochesterUSA

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