Targeting eNOS and beyond: Emerging heterogeneity of the role of endothelial Rho proteins in stroke protection

Expert Review of Neurotherapeutics

Volumn 9, Issue 8, 2009, Pages 1171-1186

  Sawada, Naoki ^b,c   Liao, James K ^a  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

^b BETH ISRAEL DEACONESS MEDICAL CENTER   (United States)

^c TOKYO MEDICAL AND DENTAL UNIVERSITY   (Japan)

Author keywords

Blood brain barrier; eNOS; GTP binding protein; Neurotrophic factors; Neurovascular unit; Rac1; Rho kinase; RhoA; Statins; Vascular endothelium

Indexed keywords

ANGIOTENSIN RECEPTOR ANTAGONIST; ARTEMIN; CORTICOSTEROID DERIVATIVE; CYTOCHALACIN D; DIPYRIDAMOLE; ENDOTHELIAL NITRIC OXIDE SYNTHASE; ESTROGEN; EXOENZYME C3; FASUDIL; GROWTH FACTOR; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; NEUROTROPHIC FACTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA AGONIST; PROTEIN INHIBITOR; RAC1 PROTEIN; RESVERATROL; RHO FACTOR; RHOA GUANINE NUCLEOTIDE BINDING PROTEIN; THYROID HORMONE; UNCLASSIFIED DRUG;

BLOOD BRAIN BARRIER; BRAIN BLOOD FLOW; BRAIN ISCHEMIA; CELL ADHESION; CELL SURVIVAL; CEREBROVASCULAR ACCIDENT; CLINICAL TRIAL; CONJUGATION; DRUG INHIBITION; ENZYME ACTIVITY; GENETIC HETEROGENEITY; HUMAN; MIDDLE CEREBRAL ARTERY OCCLUSION; MORBIDITY; NEUROPROTECTION; NONHUMAN; PLEIOTROPY; PROTEIN EXPRESSION; PROTEIN TARGETING; REVIEW; SALVAGE THERAPY; STROKE; UPREGULATION; VASCULAR ENDOTHELIUM;

ANIMALS; BLOOD-BRAIN BARRIER; ENDOTHELIUM; HUMANS; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; MODELS, BIOLOGICAL; NERVE TISSUE PROTEINS; NITRIC OXIDE SYNTHASE TYPE III; RHOA GTP-BINDING PROTEIN; STROKE; UP-REGULATION;

EID: 70349305709     PISSN: 14737175     EISSN: 17448360     Source Type: Journal    
DOI: 10.1586/ern.09.70     Document Type: Review

References (152)

1. Murphy S, Gibson CL. Nitric oxide, ischaemia and brain inflammation. Biochem. Soc. Trans. 35(Pt 5), 1133-1137 (2007). (Pubitemid 350206445)
2. Ginsberg MD. Neuroprotection for ischemic stroke: past, present and future. Neuropharmacology 55(3), 363-389 (2008).
3. Mehta SL, Manhas N, Raghubir R. Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res. Rev. 54(1), 34-66 (2007). Comprehensive overview of the cell signals that regulate neuronal cell death. (Pubitemid 46498164)
4. Schlachetzki F, Zhang Y, Boado RJ, Pardridge WM. Gene therapy of the brain: the trans-vascular approach. Neurology 62(8), 1275-1281 (2004). (Pubitemid 38526037)
5. Rudic RD, Sessa WC. Nitric oxide in endothelial dysfunction and vascular remodeling: clinical correlates and experimental links. Am. J. Hum. Genet. 64(3), 673-677 (1999).
6. Samdani AF, Dawson TM, Dawson VL. Nitric oxide synthase in models of focal ischemia. Stroke 28(6), 1283-1288 (1997).
7. Knowles RG, Moncada S. Nitric oxide synthases in mammals. Biochem. J. 298(Pt 2), 249-258 (1994).
8. Murphy S, Simmons ML, Agullo L et al. Synthesis of nitric oxide in CNS glial cells. Trends Neurosci. 16(8), 323-328 (1993). (Pubitemid 23190649)
9. Moro MA, Cardenas A, Hurtado O, Leza JC, Lizasoain I. Role of nitric oxide after brain ischaemia. Cell Calcium 36(3-4), 265-275 (2004). (Pubitemid 38992352)
10. Malinski T, Bailey F, Zhang ZG, Chopp M. Nitric oxide measured by a porphyrinic microsensor in rat brain after transient middle cerebral artery occlusion. J. Cereb. Blood Flow Metab. 13(3), 355-358 (1993). (Pubitemid 23129387)
11. Huang Z, Huang PL, Panahian N et al. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 265(5180), 1883-1885 (1994).
12. Iadecola C, Zhang F, Casey R, Nagayama M, Ross ME. Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J. Neurosci. 17(23), 9157-9164 (1997). (Pubitemid 27498443)
13. Endres M, Scott G, Namura S et al. Role of peroxynitrite and neuronal nitric oxide synthase in the activation of poly(ADP-ribose) synthetase in a murine model of cerebral ischemia-reperfusion. Neurosci. Lett. 248(1), 41-44 (1998). (Pubitemid 28267098)
14. Koppenol WH, Moreno JJ, Pryor WA, Ischiropoulos H, Beckman JS. Peroxynitrite, a cloaked oxidant formed by nitric oxide and superoxide. Chem. Res. Toxicol. 5(6), 834-842 (1992). (Pubitemid 23004874)
15. Clementi E, Brown GC, Feelisch M, Moncada S. Persistent inhibition of cell respiration by nitric oxide: crucial role of S-nitrosylation of mitochondrial complex I and protective action of glutathione. Proc. Natl Acad. Sci. USA 95(13), 7631-7636 (1998). (Pubitemid 28293304)
16. Huang Z, Huang PL, Ma J et al. Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-L-arginine. J. Cereb. Blood Flow Metab. 16(5), 981-987 (1996). (Pubitemid 26292066)
17. Lo EH, Hara H, Rogowska J et al. Temporal correlation mapping analysis of the hemodynamic penumbra in mutant mice deficient in endothelial nitric oxide synthase gene expression. Stroke 27(8), 1381-1385 (1996). (Pubitemid 26286172)
18. Dalkara T, Morikawa E, Panahian N, Moskowitz MA. Blood flow-dependent functional recovery in a rat model of focal cerebral ischemia. Am. J. Physiol. 267(2 Pt 2), H678-H683 (1994). (Pubitemid 24272487)
19. Fleming I, Busse R. Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284(1), R1-R12 (2003). (Pubitemid 36008649)
20. Fulton D, Gratton JP, Sessa WC. Post-translational control of endothelial nitric oxide synthase: why isn't calcium/calmodulin enough? J. Pharmacol. Exp. Ther. 299(3), 818-824 (2001). (Pubitemid 33104947)
21. Liu VW, Huang PL. Cardiovascular roles of nitric oxide: a review of insights from nitric oxide synthase gene disrupted mice. Cardiovasc. Res. 77(1), 19-29 (2008).
22. Dimmeler S, Fleming I, Fisslthaler B et al. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 399(6736), 601-605 (1999). (Pubitemid 29279182)
23. Fulton D, Gratton JP, McCabe TJ et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399(6736), 597-601 (1999). (Pubitemid 29279181)
24. Shaul PW. Regulation of endothelial nitric oxide synthase: location, location, location. Annu. Rev. Physiol. 64, 749-774 (2002).
25. Reinoso RF, Sanchez Navarro A, Garcia MJ, Prous JR. Preclinical pharmacokinetics of statins. Methods Find Exp. Clin. Pharmacol. 24(9), 593-613 (2002).
26. Endres M. Statins and stroke. J. Cereb. Blood Flow Metab. 25(9), 1093-1110 (2005).
27. Endres M, Laufs U, Huang Z et al. Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc. Natl Acad. Sci. USA 95(15), 8880-8885 (1998). (Pubitemid 28350583)
28. Yamada M, Huang Z, Dalkara T et al. Endothelial nitric oxide synthase-dependent cerebral blood flow augmentation by l-arginine after chronic statin treatment. J. Cereb. Blood Flow Metab. 20(4), 709-717 (2000). (Pubitemid 30217509)
29. Sironi L, Cimino M, Guerrini U et al. Treatment with statins after induction of focal ischemia in rats reduces the extent of brain damage. Arterioscler. Thromb. Vasc. Biol. 23(2), 322-327 (2003). (Pubitemid 36231947)
30. Kawashima S, Yamashita T, Miwa Y et al. HMG-CoA reductase inhibitor has protective effects against stroke events in stroke-prone spontaneously hypertensive rats. Stroke 34(1), 157-163 (2003). (Pubitemid 36070817)
31. Laufs U. Beyond lipid-lowering: effects of statins on endothelial nitric oxide. Eur J. Clin. Pharmacol. 58(11), 719-731 (2003). (Pubitemid 36399228)
32. Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J et al. Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J. Clin. Invest. 101(12), 2711-2719 (1998). (Pubitemid 28294580)
33. Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J. Biol. Chem. 273(37), 24266-24271 (1998). (Pubitemid 28435775)
34. Laufs U, Endres M, Stagliano N et al. Neuroprotection mediated by changes in the endothelial actin cytoskeleton. J. Clin. Invest. 106(1), 15-24 (2000). (Pubitemid 30437236)
35. Rikitake Y, Kim HH, Huang Z et al. Inhibition of Rho kinase (ROCK) leads to increased cerebral blood flow and stroke protection. Stroke 36(10), 2251-2257 (2005). (Pubitemid 41429255)
36. Dimmeler S, Aicher A, Vasa M et al. HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J. Clin. Invest. 108(3), 391-397 (2001). (Pubitemid 32730785)
37. Kureishi Y, Luo Z, Shiojima I et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat. Med. 6(9), 1004-1010 (2000).
38. Wolfrum S, Dendorfer A, Rikitake Y et al. Inhibition of Rho-kinase leads to rapid activation of phosphatidylinositol 3-kinase/protein kinase Akt and cardiovascular protection. Arterioscler. Thromb. Vasc. Biol. 24(10), 1842-1847 (2004).
39. Shin HK, Salomone S, Potts EM et al. Rho-kinase inhibition acutely augments blood flow in focal cerebral ischemia via endothelial mechanisms. J. Cereb. Blood Flow Metab. 27(5), 998-1009 (2007). (Pubitemid 46659030)
40. Atochin DN, Wang A, Liu VW et al. The phosphorylation state of eNOS modulates vascular reactivity and outcome of cerebral ischemia in vivo. J. Clin. Invest. 117(7), 1961-1967 (2007). Elegant study that used mice transgenically expressing phosphomimetic or phosphoresistant endothelial nitric oxide synthase in endothelial cells (ECs), demonstrating the in vivo relevance of serine 1179 phosphorylation of eNOS in stroke protection.
41. Asahi M, Huang Z, Thomas S et al. Protective effects of statins involving both eNOS and tPA in focal cerebral ischemia. J. Cereb. Blood Flow Metab. 25(6), 722-729 (2005). (Pubitemid 40705607)
42. Zhang L, Zhang ZG, Ding GL et al. Multitargeted effects of statin-enhanced thrombolytic therapy for stroke with recombinant human tissue-type plasminogen activator in the rat. Circulation 112(22), 3486-3494 (2005). (Pubitemid 43739565)
43. Mayanagi K, Katakam PV, Gaspar T, Domoki F, Busija DW. Acute treatment with rosuvastatin protects insulin resistant (C57BL/6J ob/ob) mice against transient cerebral ischemia. J. Cereb. Blood Flow Metab. 28(12), 1927-1935 (2008).
44. Taylor WC, Landau WM. Atherosclerosis and stroke. Ann. Neurol. 28(1), 108-109 (1990).
45. Atkins D, Psaty BM, Koepsell TD, Longstreth WT Jr, Larson EB. Cholesterol reduction and the risk for stroke in men. A meta-analysis of randomized, controlled trials. Ann. Intern. Med. 119(2), 136-145 (1993). (Pubitemid 23286480)
46. Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total mortality: an overview of randomized trials. JAMA 278(4), 313-321 (1997).
47. Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N. Engl. J. Med. 320(14), 904-910 (1989). (Pubitemid 19101595)
48. Blood pressure, cholesterol, and stroke in eastern Asia. Eastern Stroke and Coronary Heart Disease Collaborative Research Group. Lancet 352(9143), 1801-1807 (1998).
49. Hachinski V, Graffagnino C, Beaudry M et al. Lipids and stroke: a paradox resolved. Arch. Neurol. 53(4), 303-308 (1996).
50. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360(9326), 7-22 (2002).
51. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344(8934), 1383-1389 (1994).
52. Sacks FM, Pfeffer MA, Moye LA et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N. Engl. J. Med. 335(14), 1001-1009 (1996).
53. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels: the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N. Engl. J. Med. 339(19), 1349-1357 (1998).
54. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation 97(15), 1440-1445 (1998).
55. Byington RP, Davis BR, Plehn JF et al. Reduction of stroke events with pravastatin: the prospective pravastatin pooling (PPP) project. Circulation 103(3), 387-392 (2001).
56. Collins R, Armitage J, Parish S, Sleight P, Peto R. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet 363(9411), 757-767 (2004).
57. Shepherd J, Cobbe SM, Ford I et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N. Engl. J. Med. 333(20), 1301-1307 (1995).
58. Shepherd J, Blauw GJ, Murphy MB et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 360(9346), 1623-1630 (2002). (Pubitemid 35379733)
59. Sever PS, Dahlof B, Poulter NR et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian cardiac outcomes trial - lipid lowering arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 361(9364), 1149-1158 (2003). (Pubitemid 36398384)
60. Jonsson N, Asplund K. Does pretreatment with statins improve clinical outcome after stroke? A pilot case-referent study. Stroke 32(5), 1112-1115 (2001). (Pubitemid 32825793)
61. Thomas M, Mann J. Increased thrombotic vascular events after change of statin. Lancet 352(9143), 1830-1831 (1998).
62. Heeschen C, Hamm CW, Laufs U et al. Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation 105(12), 1446-1452 (2002). (Pubitemid 34263276)
63. Amarenco P, Bogousslavsky J, Callahan A, 3rd et al. High-dose atorvastatin after stroke or transient ischemic attack. N. Engl. J. Med. 355(6), 549-559 (2006). (Pubitemid 44202151)
64. Goldstein LB, Amarenco P, Szarek M et al. Hemorrhagic stroke in the stroke prevention by aggressive reduction in cholesterol levels study. Neurology 70(24 Pt 2), 2364-2370 (2008).
65. Vergouwen MD, de Haan RJ, Vermeulen M, Roos YB. Statin treatment and the occurrence of hemorrhagic stroke in patients with a history of cerebrovascular disease. Stroke 39(2), 497-502 (2008). (Pubitemid 351619482)
66. Bang OY, Saver JL, Liebeskind DS et al. Cholesterol level and symptomatic hemorrhagic transformation after ischemic stroke thrombolysis. Neurology 68(10), 737-742 (2007).
67. Mascitelli L, Pezzetta F. Low LDL cholesterol, statins, and brain hemorrhage: should we worry? Neurology 69(10), 1061-1062 (2007). (Pubitemid 47366062)
68. Kim HH, Sawada N, Soydan G et al. Additive effects of statin and dipyridamole on cerebral blood flow and stroke protection. J. Cereb. Blood Flow Metab. 28(7), 1285-1293 (2008). (Pubitemid 351896647)
69. Nishimura Y, Ito T, Saavedra JM. Angiotensin II AT(1) blockade normalizes cerebrovascular autoregulation and reduces cerebral ischemia in spontaneously hypertensive rats. Stroke 31(10), 2478-2486 (2000). (Pubitemid 30740561)
70. Saavedra JM, Benicky J, Zhou J. Mechanisms of the anti-ischemic effect of angiotensin II AT(1) receptor antagonists in the brain. Cell Mol. Neurobiol. 26(7-8), 1099-1111 (2006). (Pubitemid 44924033)
71. Culman J, Zhao Y, Gohlke P, Herdegen T. PPAR-g: therapeutic target for ischemic stroke. Trends Pharmacol. Sci. 28(5), 244-249 (2007). (Pubitemid 46661003)
72. Chu K, Lee ST, Koo JS et al. Peroxisome proliferator-activated receptor-γ-agonist, rosiglitazone, promotes angiogenesis after focal cerebral ischemia. Brain Res. 1093(1), 208-218 (2006). (Pubitemid 43946402)
73. Tsai SK, Hung LM, Fu YT et al. Resveratrol neuroprotective effects during focal cerebral ischemia injury via nitric oxide mechanism in rats. J. Vasc. Surg. 46(2), 346-353 (2007).
74. Endres M, Gertz K, Lindauer U et al. Mechanisms of stroke protection by physical activity. Ann. Neurol. 54(5), 582-590 (2003). (Pubitemid 37346064)
75. Sasaki Y, Noguchi T, Yamamoto E et al. Effects of voluntary exercise on cerebral thrombosis and endothelial function in spontaneously hypertensive rats (SHRSP/Izm). Clin. Exp. Pharmacol. Physiol. 31(Suppl. 2), S47-S48 (2004).
76. Laufs U, Werner N, Link A et al. Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis. Circulation 109(2), 220-226 (2004). (Pubitemid 38114143)
77. 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. 99(10), 1132-1140 (2006). (Pubitemid 44729938)
78. Hafezi-Moghadam A, Simoncini T, Yang Z et al. Acute cardiovascular protective effects of corticosteroids are mediated by nontranscriptional activation of endothelial nitric oxide synthase. Nat. Med. 8(5), 473-479 (2002). (Pubitemid 34546749)
79. Limbourg FP, Huang Z, Plumier JC et al. Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids. J. Clin. Invest. 110(11), 1729-1738 (2002). (Pubitemid 35424251)
80. Simoncini T, Hafezi-Moghadam A, Brazil DP et al. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 407(6803), 538-541 (2000). (Pubitemid 30746711)
81. Hiroi Y, Kim HH, Ying H et al. Rapid nongenomic actions of thyroid hormone. Proc. Natl Acad. Sci. USA 103(38), 14104-14109 (2006). (Pubitemid 44452987)
82. Murohara T, Asahara T, Silver M et al. Nitric oxide synthase modulates angiogenesis in response to tissue ischemia. J. Clin. Invest. 101(11), 2567-2578 (1998). (Pubitemid 28270451)
83. Aicher A, Heeschen C, Mildner-Rihm C et al. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat. Med. 9(11), 1370-1376 (2003). (Pubitemid 37466185)
84. Ovbiagele B, Saver JL, Starkman S et al. Statin enhancement of collateralization in acute stroke. Neurology 68(24), 2129-2131 (2007). (Pubitemid 46912132)
85. Chen J, Zacharek A, Zhang C et al. Endothelial nitric oxide synthase regulates brain-derived neurotrophic factor expression and neurogenesis after stroke in mice. J. Neurosci. 25(9), 2366-2375 (2005). (Pubitemid 40322278)
86. Lee CD, Folsom AR, Blair SN. Physical activity and stroke risk: a meta-analysis. Stroke 34(10), 2475-2481 (2003).
87. Di Castelnuovo A, Rotondo S, Iacoviello L, Donati MB, De Gaetano G. Meta-analysis of wine and beer consumption in relation to vascular risk. Circulation 105(24), 2836-2844 (2002). (Pubitemid 34666095)
88. Thomas D, Bath PM, Lees K et al. Glyceryl trinitrate vs. control, and continuing vs. stopping temporarily prior antihypertensive therapy, in acute stroke: rationale and design of the Efficacy of Nitric Oxide in Stroke (ENOS) trial (ISRCTN99414122). Int. J. Stroke 1(4), 245-249 (2006). (Pubitemid 44541740)
89. Hassan A, Gormley K, O'Sullivan M et al. Endothelial nitric oxide gene haplotypes and risk of cerebral small-vessel disease. Stroke 35(3), 654-659 (2004). (Pubitemid 38280836)
90. Wang XL, Wang J. Endothelial nitric oxide synthase gene sequence variations and vascular disease. Mol. Genet. Metab. 70(4), 241-251 (2000). (Pubitemid 30736425)
91. Starke RM, Kim GH, Komotar RJ et al. Endothelial nitric oxide synthase gene single-nucleotide polymorphism predicts cerebral vasospasm after aneurysmal subarachnoid hemorrhage. J. Cereb. Blood Flow Metab. 28(6), 1204-1211 (2008).
92. Ko NU, Rajendran P, Kim H et al. Endothelial nitric oxide synthase polymorphism (-786T - C) and increased risk of angiographic vasospasm after aneurysmal subarachnoid hemorrhage. Stroke 39(4), 1103-1108 (2008).
93. McGirt MJ, Lynch JR, Parra A et al. Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage. Stroke 33(12), 2950-2956 (2002). (Pubitemid 35462871)
94. White BC, Sullivan JM, DeGracia DJ et al. Brain ischemia and reperfusion: molecular mechanisms of neuronal injury. J. Neurol. Sci. 179(S 1-2), 1-33 (2000).
95. Lok J, Gupta P, Guo S et al. Cell-cell signaling in the neurovascular unit. Neurochem. Res. 32(12), 2032-2045 (2007). In-depth review presenting the conceptual framework of the neurovascular unit.
96. Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat. Rev. Neurosci. 7(1), 41-53 (2006). Excellent review summarizing the emerging EC-glial interaction underlying the BBB.
97. Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Nat. Rev. Neurosci. 4(5), 399-415 (2003). Comprehensive view of the neurovascular unit and its implication in diseases.
98. Wu D. Neuroprotection in experimental stroke with targeted neurotrophins. NeuroRx 2(1), 120-128 (2005). (Pubitemid 40128032)
99. Lindsay RM. Neuron saving schemes. Nature 373(6512), 289-290 (1995).
100. Kitagawa H, Hayashi T, Mitsumoto Y et al. Reduction of ischemic brain injury by topical application of glial cell line-derived neurotrophic factor after permanent middle cerebral artery occlusion in rats. Stroke 29(7), 1417-1422 (1998). (Pubitemid 28300081)
101. Tomac A, Lindqvist E, Lin LF et al. Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature 373(6512), 335-339 (1995).
102. Harvey BK, Hoffer BJ, Wang Y. Stroke and TGF-β proteins: glial cell line-derived neurotrophic factor and bone morphogenetic protein. Pharmacol. Ther. 105(2), 113-125 (2005).
103. Lang AE, Gill S, Patel NK et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann. Neurol. 59(3), 459-466 (2006). (Pubitemid 43358066)
104. Patel NK, Bunnage M, Plaha P et al. Intraputamenal infusion of glial cell line-derived neurotrophic factor in PD: a two-year outcome study. Ann. Neurol. 57(2), 298-302 (2005). (Pubitemid 40179870)
105. Leventhal C, Rafii S, Rafii D, Shahar A, Goldman SA. Endothelial trophic support of neuronal production and recruitment from the adult mammalian subependyma. Mol. Cell Neurosci. 13(6), 450-464 (1999). (Pubitemid 29337211)
106. 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. 25(2), 281-290 (2005). (Pubitemid 40171209)
107. Shen Q, Goderie SK, Jin L et al. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304(5675), 1338-1340 (2004). Seminal work demonstrating the neuronal stem cell dependence on ECs. (Pubitemid 38697433)
108. del Zoppo GJ, Mabuchi T. Cerebral microvessel responses to focal ischemia. J. Cereb. Blood Flow Metab. 23(8), 879-894 (2003). (Pubitemid 36959394)
109. Cunningham LA, Wetzel M, Rosenberg GA. Multiple roles for MMPs and TIMPs in cerebral ischemia. Glia 50(4), 329-339 (2005). (Pubitemid 40780839)
110. Lipton P. Ischemic cell death in brain neurons. Physiol. Rev. 79(4), 1431-1568 (1999). (Pubitemid 29473320)
111. Jiang X, Namura S, Nagata I. Matrix metalloproteinase inhibitor KB-R7785 attenuates brain damage resulting from permanent focal cerebral ischemia in mice. Neurosci. Lett. 305(1), 41-44 (2001). (Pubitemid 32436470)
112. Heasman SJ, Ridley AJ. Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat. Rev. Mol. Cell Biol. 9(9), 690-701 (2008).
113. Sawada N, Salomone S, Kim HH, Kwiatkowski DJ, Liao JK. Regulation of endothelial nitric oxide synthase and postnatal angiogenesis by Rac1. Circ. Res. 103(4), 360-368 (2008).
114. Tan W, Palmby TR, Gavard J et al. An essential role for Rac1 in endothelial cell function and vascular development. FASEB J. 22(6), 1829-1838 (2008).
115. Sawada N, Kim HH, Moskowitz MA, Liao JK. Rac1 is a critical mediator of endothelium-derived neurotrophic activity. Sci. Signal 2(61), ra10 (2009).
116. Bierl C, Voetsch B, Jin RC, Handy DE, Loscalzo J. Determinants of human plasma glutathione peroxidase (GPx-3) expression. J. Biol. Chem. 279(26), 26839-26845 (2004). (Pubitemid 38812517)
117. Voetsch B, Jin RC, Bierl C et al. Promoter polymorphisms in the plasma glutathione peroxidase (GPx-3) gene: a novel risk factor for arterial ischemic stroke among young adults and children. Stroke 38(1), 41-49 (2007). (Pubitemid 46035604)
118. Gabai VL, Sherman MY. Invited review: Interplay between molecular chaperones and signaling pathways in survival of heat shock. J. Appl. Physiol. 92(4), 1743-1748 (2002).
119. Kamradt MC, Chen F, Sam S, Cryns VL. The small heat shock protein α B-crystallin negatively regulates apoptosis during myogenic differentiation by inhibiting caspase-3 activation. J. Biol. Chem. 277(41), 38731-38736 (2002). (Pubitemid 35154735)
120. Beere HM. Stressed to death: regulation of apoptotic signaling pathways by the heat shock proteins. Sci. STKE 2001(93), RE1 (2001).
121. Bornstein P, Agah A, Kyriakides TR. The role of thrombospondins 1 and 2 in the regulation of cell-matrix interactions, collagen fibril formation, and the response to injury. Int. J. Biochem. Cell Biol. 36(6), 1115-1125 (2004). (Pubitemid 38501563)
122. Bornstein P. Thrombospondins as matricellular modulators of cell function. J. Clin. Invest. 107(8), 929-934 (2001). (Pubitemid 32323400)
123. Baloh RH, Tansey MG, Lampe PA et al. Artemin, a novel member of the GDNF ligand family, supports peripheral and central neurons and signals through the GFRα3-RET receptor complex. Neuron 21(6), 1291-1302 (1998).
124. Reuss B, von Bohlen und Halbach O. Fibroblast growth factors and their receptors in the central nervous system. Cell Tissue Res. 313(2), 139-157 (2003). (Pubitemid 37129946)
125. Junier MP. What role(s) for TGFa in the central nervous system? Prog Neurobiol, 62(5), 443-473 (2000).
126. Wang Y, Chang CF, Morales M, Chiang YH, Hoffer J. Protective effects of glial cell line-derived neurotrophic factor in ischemic brain injury. Ann. NY Acad. Sci. 962, 423-437 (2002). (Pubitemid 34592330)
127. Honma Y, Araki T, Gianino S et al. Artemin is a vascular-derived neurotropic factor for developing sympathetic neurons. Neuron 35(2), 267-282 (2002). (Pubitemid 34876730)
128. Damon DH, Teriele JA, Marko SB. Vascular-derived artemin: a determinant of vascular sympathetic innervation? Am. J. Physiol. Heart Circ. Physiol. 293(1), H266-H273 (2007).
129. Bespalov MM, Saarma M. GDNF family receptor complexes are emerging drug targets. Trends Pharmacol. Sci. 28(2), 68-74 (2007). (Pubitemid 46161837)
130. Baloh RH, Gorodinsky A, Golden JP et al. GFRa3 is an orphan member of the GDNF/neurturin/persephin receptor family. Proc. Natl Acad. Sci. USA 95(10), 5801-5806 (1998). (Pubitemid 28224177)
131. Rosenblad C, Gronborg M, Hansen C et al. In vivo protection of nigral dopamine neurons by lentiviral gene transfer of the novel GDNF-family member neublastin/artemin. Mol. Cell Neurosci. 15(2), 199-214 (2000). (Pubitemid 30109122)
132. Ducray A, Krebs SH, Schaller B et al. GDNF family ligands display distinct action profiles on cultured GABAergic and serotonergic neurons of rat ventral mesencephalon. Brain Res. 1069(1), 104-112 (2006). (Pubitemid 43149274)
133. Bonde C, Kristensen BW, Blaabjerg M et al. GDNF and neublastin protect against NMDA-induced excitotoxicity in hippocampal slice cultures. Neuroreport 11(18), 4069-4073 (2000). (Pubitemid 32038805)
134. Sakai T, Johnson KJ, Murozono M et al. Plasma fibronectin supports neuronal survival and reduces brain injury following transient focal cerebral ischemia but is not essential for skin-wound healing and hemostasis. Nat. Med. 7(3), 324-330 (2001). (Pubitemid 32224348)
135. Reuss B, Dono R, Unsicker K. Functions of fibroblast growth factor (FGF)-2 and FGF-5 in astroglial differentiation and blood-brain barrier permeability: evidence from mouse mutants. J. Neurosci. 23(16), 6404-6412 (2003). (Pubitemid 36909865)
136. Unsicker K, Krieglstein K. Co-activation of TGF-β and cytokine signaling pathways are required for neurotrophic functions. Cytokine Growth Factor Rev. 11(1-2), 97-102 (2000). (Pubitemid 30169730)
137. Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. J. Comp. Neurol. 425(4), 479-494 (2000).
138. Kumar P, Wu H, McBride JL et al. Transvascular delivery of small interfering RNA to the central nervous system. Nature 448(7149), 39-43 (2007). (Pubitemid 47037001)
139. Spencer BJ, Verma IM. Targeted delivery of proteins across the blood-brain barrier. Proc. Natl Acad. Sci. USA 104(18), 7594-7599 (2007).
140. Guo S, Kim WJ, Lok J et al. Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons. Proc. Natl Acad. Sci. USA 105(21), 7582-7587 (2008). (Pubitemid 351830061)
141. Kennedy J, Hill MD, Ryckborst KJ et al. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. Lancet Neurol. 6(11), 961-969 (2007). (Pubitemid 47562312)
142. Bogousslavsky J, Victor SJ, Salinas EO et al. Fiblast (trafermin) in acute stroke: results of the European-Australian Phase II/III safety and efficacy trial. Cerebrovasc. Dis. 14(3-4), 239-251 (2002). (Pubitemid 36151425)
143. Fisher M, Meadows ME, Do T et al. Delayed treatment with intravenous basic fibroblast growth factor reduces infarct size following permanent focal cerebral ischemia in rats. J. Cereb. Blood Flow Metab. 15(6), 953-959 (1995).
144. Cleaver O, Melton DA. Endothelial signaling during development. Nat. Med. 9(6), 661-668 (2003). Important review discussing the general role of EC cues in tissue development and function.
145. Gao Y, Dickerson JB, Guo F, Zheng J, Zheng Y. Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc. Natl Acad. Sci. USA 101(20), 7618-7623 (2004). (Pubitemid 38658078)
146. Tsukahara T, Yonekawa Y, Tanaka K et al. The role of brain-derived neurotrophic factor in transient forebrain ischemia in the rat brain. Neurosurgery 34(2), 323-331 (1994). (Pubitemid 24044111)
147. Prehn JH, Backhauss C, Krieglstein J. Transforming growth factor-β1 prevents glutamate neurotoxicity in rat neocortical cultures and protects mouse neocortex from ischemic injury in vivo. J. Cereb. Blood Flow Metab. 13(3), 521-525 (1993). (Pubitemid 23129406)
148. Wang Y, Chang CF, Morales M et al. Bone morphogenetic protein-6 reduces ischemia-induced brain damage in rats. Stroke 32(9), 2170-2178 (2001). (Pubitemid 32868118)
149. Liu Y, Belayev L, Zhao W et al. The effect of bone morphogenetic protein-7 (BMP-7) on functional recovery, local cerebral glucose utilization and blood flow after transient focal cerebral ischemia in rats. Brain Res. 905(1-2), 81-90 (2001). (Pubitemid 32553841)
150. Yao DL, Masonic K, Petullo D et al. Pretreatment with intravenous FGF-13 reduces infarct volume and ameliorates neurological deficits following focal cerebral ischemia in rats. Brain Res. 818(1), 140-146 (1999). (Pubitemid 29227293)
151. Ellsworth JL, Garcia R, Yu J, Kindy MS. Fibroblast growth factor-18 reduced infarct volumes and behavioral deficits after transient occlusion of the middle cerebral artery in rats. Stroke 34(6), 1507-1512 (2003). (Pubitemid 36693526)
152. Justicia C, Perez-Asensio FJ, Burguete MC, Salom JB, Planas AM. Administration of transforming growth factor-a reduces infarct volume after transient focal cerebral ischemia in the rat. J. Cereb. Blood Flow Metab. 21(9), 1097-1104 (2001). (Pubitemid 32823745)