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Rho kinase as a target for cerebral vascular disorders

    Lisa M Bond

    BioAxone BioSciences, Inc., 10 Rogers Street, Suite 101, Kendall Square, Cambridge, MA 02142, USA

    Laboratory of Molecular Physiology, National Heart, Lung & Blood Institute, Bethesda, MD 20892, USA

    ,
    James R Sellers

    Laboratory of Molecular Physiology, National Heart, Lung & Blood Institute, Bethesda, MD 20892, USA

    &
    Lisa McKerracher

    *Author for correspondence:

    E-mail Address: lmck@bioaxonebio.com

    BioAxone BioSciences, Inc., 10 Rogers Street, Suite 101, Kendall Square, Cambridge, MA 02142, USA

    Published Online:https://doi.org/10.4155/fmc.15.45

    The development of novel pharmaceutical treatments for disorders of the cerebral vasculature is a serious unmet medical need. These vascular disorders are typified by a disruption in the delicate Rho signaling equilibrium within the blood vessel wall. In particular, Rho kinase overactivation in the smooth muscle and endothelial layers of the vessel wall results in cytoskeletal modifications that lead to reduced vascular integrity and abnormal vascular growth. Rho kinase is thus a promising target for the treatment of cerebral vascular disorders. Indeed, preclinical studies indicate that Rho kinase inhibition may reduce the formation/growth/rupture of both intracranial aneurysms and cerebral cavernous malformations.

    References

    • 1 Bederson JB, Connolly ES Jr, Batjer HH et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a statement for healthcare professionals from a special writing group of the stroke council, American heart association. Stroke 40(3), 994–1025 (2009).
    • 2 Schievink WI. Intracranial aneurysms. N. Engl. J. Med. 336(1), 28–40 (1997).
    • 3 Campbell PG, Jabbour P, Yadla S, Awad IA. Emerging clinical imaging techniques for cerebral cavernous malformations: a systematic review. Neurosurg. Focus 29(3), E6 (2010).
    • 4 Gross BA, Du R. Diagnosis and treatment of vascular malformations of the brain. Curr. Treat. Options Neurol. 16(1), 279 (2014).
    • 5 Wiebers DO, Whisnant JP, Huston J 3rd et al. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 362(9378), 103–110 (2003).
    • 6 Loirand G, Guérin P, Pacaud P. Rho kinases in cardiovascular physiology and pathophysiology. Circ. Res. 98(3), 322–334 (2006).
    • 7 Hall A. Gtp-binding proteins and the regulation of the actin cytoskeleton. Ann. Rev. Cell Biol. 10, 31–54 (1996).
    • 8 Zlokovic BV. The blood–brain barrier in health and chronic neurodegenerative disorders. Neuron 57(2), 178–201 (2008).
    • 9 Stanimirovic DB, Friedman A. Pathophysiology of the neurovascular unit: disease cause or consequence? J. Cereb. Blood Flow Metab. 32(7), 1207–1221 (2012).
    • 10 Neuwelt EA, Bauer B, Fahlke C et al. Engaging neuroscience to advance translational research in brain barrier biology. Nat. Rev. Neurosci. 12(3), 169–182 (2011).
    • 11 Stamatovic SM, Keep RF, Andjelkovic AV. Brain endothelial cell-cell junctions: how to “open” the blood brain barrier. Curr. Neuropharmacol. 6(3), 179–192 (2008).
    • 12 Stamatovic SM, Keep RF, Kunkel SL, Andjelkovic AV. Potential role of mcp-1 in endothelial cell tight junctionopening': signaling via Rho and Rho kinase. J. Cell Sci. 116(22), 4615–4628 (2003).
    • 13 Hartsock A, Nelson WJ. Adherens and tight junctions: Structure, function and connections to the actin cytoskeleton. Biochim. Biophys. Acta 1778(3), 660–669 (2008).
    • 14 Hellström M, Gerhardt H, Kalén M et al. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J. Cell Biol. 153(3), 543–554 (2001).
    • 15 Gerhardt H, Wolburg H, Redies C. N‐cadherin mediates pericytic‐endothelial interaction during brain angiogenesis in the chicken. Dev. Dyn. 218(3), 472–479 (2000).
    • 16 Dore-Duffy P. Pericytes: pluripotent cells of the blood–brain barrier. Curr. Pharm. Design 14(16), 1581–1593 (2008).
    • 17 Rucker HK, Wynder HJ, Thomas WE. Cellular mechanisms of CNS pericytes. Brain Res. Bull. 51(5), 363–369 (2000).
    • 18 Matsui T, Amano M, Yamamoto T et al. Rho-associated kinase, a novel serine/threonine kinase, as a putative target for small gtp binding protein Rho. EMBO J. 15(9), 2208–2216 (1996).
    • 19 Ishizaki T, Maekawa M, Fujisawa K et al. The small gtp-binding protein Rho binds to and activates a 160 kda ser/thr protein kinase homologous to myotonic dystrophy kinase. EMBO J. 15(8), 1885–1893 (1996).
    • 20 Mueller BK, Mack H, Teusch N. Rho kinase, a promising drug target for neurological disorders. Nat. Rev. Drug Discov. 4(5), 387–398 (2005).
    • 21 Shimada H, Rajagopalan LE. Rho kinase-2 activation in human endothelial cells drives lysophosphatidic acid-mediated expression of cell adhesion molecules via nf-κb p65. J. Biol. Chem. 285(17), 12536–12542 (2010).
    • 22 Hyun Lee J, Zheng Y, Bornstadt D et al. Selective rock2 inhibition in focal cerebral ischemia. Ann. Clin. Transl. Neurol. 1(1), 2–14 (2014).
    • 23 Riento K, Ridley AJ. Rocks: multifunctional kinases in cell behaviour. Nat. Rev. Mol. Cell Biol. 4(6), 446–456 (2003).
    • 24 Amin E, Dubey BN, Zhang SC et al. Rho-kinase: regulation, (dys)function, and inhibition. Biol. Chem. 394(11), 1399–1410 (2013).
    • 25 Kureishi Y, Kobayashi S, Amano M et al. Rho-associated kinase directly induces smooth muscle contraction through myosin light chain phosphorylation. J. Biol. Chem. 272(19), 12257–12260 (1997).
    • 26 Kawano Y, Fukata Y, Oshiro N et al. Phosphorylation of myosin-binding subunit (mbs) of myosin phosphatase by Rho-kinase in vivo. J. Cell Sci. 147(5), 1023–1038 (1999).
    • 27 Velasco G, Armstrong C, Morrice N, Frame S, Cohen P. Phosphorylation of the regulatory subunit of smooth muscle protein phosphatase 1m at thr850 induces its dissociation from myosin. FEBS Lett. 527(1–3), 101–104 (2002).
    • 28 Satoh K, Fukumoto Y, Shimokawa H. Rho-kinase: Important new therapeutic target in cardiovascular diseases. Am. J. Physiol. Heart Circ. Physiol. 301(2), H287–H296 (2011).
    • 29 Katoh K, Kano Y, Amano M, Onishi H, Kaibuchi K, Fujiwara K. Rho-kinase-mediated contraction of isolated stress fibers. J. Cell Sci. 153(3), 569–584 (2001).
    • 30 Koyama M, Ito M, Feng J et al. Phosphorylation of cpi-17, an inhibitory phosphoprotein of smooth muscle myosin phosphatase, by Rho-kinase. FEBS Lett. 475(3), 197–200 (2000).
    • 31 Terry S, Nie M, Matter K, Balda MS. Rho signaling and tight junction functions. Physiology (Bethesda) 25(1), 16–26 (2010).
    • 32 Stamatovic SM, Keep RF, Kunkel SL, Andjelkovic AV. Potential role of mcp-1 in endothelial cell tight junction ‘opening’: signaling via Rho and Rho kinase. J. Cell Sci. 116(Pt 22), 4615–4628 (2003).
    • 33 Yamamoto M, Ramirez SH, Sato S et al. Phosphorylation of claudin-5 and occludin by Rho kinase in brain endothelial cells. Am. J. Pathol. 172(2), 521–533 (2008).
    • 34 Harris AR, Daeden A, Charras GT. Formation of adherens junctions leads to the emergence of a tissue-level tension in epithelial monolayers. J. Cell Sci. 127(Pt 11), 2507–2517 (2014).
    • 35 Sahai E, Marshall CJ. Rock and dia have opposing effects on adherens junctions downstream of Rho. Nat. Cell Biol. 4(6), 408–415 (2002).
    • 36 Shibuya M, Hirai S, Seto M, Satoh S, Ohtomo E. Fasudil Ischemic Stroke Study G. Effects of fasudil in acute ischemic stroke: results of a prospective placebo-controlled double-blind trial. J. Neurol. Sci. 238(1–2), 31–39 (2005).
    • 37 Uehata M, Ishizaki T, Satoh H et al. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature 389(6654), 990–994 (1997).
    • 38 Davies SP, Reddy H, Caivano M, Cohen P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. J. 351(Pt 1), 95–105 (2000).
    • 39 Tamura M, Nakao H, Yoshizaki H et al. Development of specific Rho-kinase inhibitors and their clinical application. Biochim. Biophys. Acta 1754(1–2), 245–252 (2005).
    • 40 Lu Q, Longo FM, Zhou H, Massa SM, Chen YH. Signaling through Rho gtpase pathway as viable drug target. Curr. Med. Chem. 16(11), 1355–1365 (2009).
    • 41 Loirand G, Guerin P, Pacaud P. Rho kinases in cardiovascular physiology and pathophysiology. Circ. Res. 98(3), 322–334 (2006).
    • 42 Satoh K, Fukumoto Y, Shimokawa H. Rho-kinase: important new therapeutic target in cardiovascular diseases. Am. J. Physiol. Heart Circ. Physiol. 301(2), H287–296 (2011).
    • 43 Tatsumi E, Yamanaka H, Kobayashi K, Yagi H, Sakagami M, Noguchi K. Rhoa/rock pathway mediates p38 mapk activation and morphological changes downstream of p2y12/13 receptors in spinal microglia in neuropathic pain. Glia 63(2), 216–228 (2014).
    • 44 Walters CE, Pryce G, Hankey DJ et al. Inhibition of Rho gtpases with protein prenyltransferase inhibitors prevents leukocyte recruitment to the central nervous system and attenuates clinical signs of disease in an animal model of multiple sclerosis. J. Immunol. 168(8), 4087–4094 (2002).
    • 45 Lehmann M, Fournier AE, Selles-Navarro I et al. Inactivation of the small gtp-binding protein Rho promotes cns axon regeneration. J. Neurosci 19, 7537–7547 (1999).
    • 46 Lord-Fontaine S, Yang F, Diep Q et al. Local inhibition of Rho signaling by cell-permeable recombinant protein ba-210 prevents secondary damage and promotes functional recovery following acute spinal cord injury. J. Neurotrauma 25(11), 1309–1322 (2008).
    • 47 Lee JH, Zheng Y, Von Bornstadt D et al. Selective rock2 inhibition in focal cerebral ischemia. Ann. Clin. Transl. Neurol. 1(1), 2–14 (2014).
    • 48 Mukai Y, Shimokawa H, Matoba T et al. Involvement of Rho-kinase in hypertensive vascular disease: a novel therapeutic target in hypertension. FASEB J. 15(6), 1062–1064 (2001).
    • 49 Mori-Kawabe M, Tsushima H, Fujimoto S, Tada T, Ito J. Role of Rho/Rho-kinase and no/cgmp signaling pathways in vascular function prior to atherosclerosis. J. Atheroscler. Thromb. 16(6), 722–732 (2009).
    • 50 Plummer NW, Zawistowski JS, Marchuk DA. Genetics of cerebral cavernous malformations. Curr. Neurol. Neurosci. Rep. 5(5), 391–396 (2005).
    • 51 Al-Holou WN, O'lynnger TM, Pandey AS et al. Natural history and imaging prevalence of cavernous malformations in children and young adults. J. Neurosurg. Pediatr. 9(2), 198–205 (2012).
    • 52 Del Curling O Jr, Kelly DL Jr, Elster AD, Craven TE. An analysis of the natural history of cavernous angiomas. J. Neurosurg. 75(5), 702–708 (1991).
    • 53 Robinson JR, Awad IA, Little JR. Natural history of the cavernous angioma. J. Neurosurg. 75(5), 709–714 (1991).
    • 54 Stockton RA, Shenkar R, Awad IA, Ginsberg MH. Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity. J. Exp. Med. 207(4), 881–896 (2010).
    • 55 Morrison L, Akers A. Cerebral Cavernous Malformations, Familial. University of Washington, Seattle WA. (2003).
    • 56 Akers AL, Johnson E, Steinberg GK, Zabramski JM, Marchuk DA. Biallelic somatic and germline mutations in cerebral cavernous malformations (ccms): evidence for a two-hit mechanism of ccm pathogenesis. Hum. Mol. Genet. 18(5), 919–930 (2009).
    • 57 Whitehead KJ, Chan AC, Navankasattusas S et al. The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho gtpases. Nat. Med. 15(2), 177–184 (2009).
    • 58 Zawistowski JS, Stalheim L, Uhlik MT et al. Ccm1 and ccm2 protein interactions in cell signaling: implications for cerebral cavernous malformations pathogenesis. Hum. Mol. Genet. 14(17), 2521–2531 (2005).
    • 59 Hilder TL, Malone MH, Bencharit S et al. Proteomic identification of the cerebral cavernous malformation signaling complex. J. Proteome Res. 6(11), 4343–4355 (2007).
    • 60 Leblanc GG, Golanov E, Awad IA, Young WL. Biology of vascular malformations of the brain NWC. Biology of vascular malformations of the brain. Stroke 40(12), e694–702 (2009).
    • 61 Faurobert E, Albiges-Rizo C. Recent insights into cerebral cavernous malformations: a complex jigsaw puzzle under construction. FEBS J. 277(5), 1084–1096 (2010).
    • 62 Bergametti F, Denier C, Labauge P et al. Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am. J. Hum. Genet. 76(1), 42–51 (2005).
    • 63 Denier C, Labauge P, Brunereau L et al. Clinical features of cerebral cavernous malformations patients with krit1 mutations. Ann. Neurol. 55(2), 213–220 (2004).
    • 64 Wong JH, Awad IA, Kim JH. Ultrastructural pathological features of cerebrovascular malformations: a preliminary report. Neurosurgery 46(6), 1454–1459 (2000).
    • 65 Clatterbuck RE, Eberhart CG, Crain BJ, Rigamonti D. Ultrastructural and immunocytochemical evidence that an incompetent blood–brain barrier is related to the pathophysiology of cavernous malformations. J. Neurol. Neurosurg. Psychiatry 71(2), 188–192 (2001).
    • 66 Tu J, Stoodley MA, Morgan MK, Storer KP. Ultrastructural characteristics of hemorrhagic, nonhemorrhagic, and recurrent cavernous malformations. J. Neurosurg. 103(5), 903–909 (2005).
    • 67 Tanriover G, Sozen B, Seker A, Kilic T, Gunel M, Demir N. Ultrastructural analysis of vascular features in cerebral cavernous malformations. Clin. Neurol. Neurosurg. 115(4), 438–444 (2013).
    • 68 Bertalanffy H, Benes L, Miyazawa T, Alberti O, Siegel AM, Sure U. Cerebral cavernomas in the adult. Review of the literature and analysis of 72 surgically treated patients. Neurosurg. Rev. 25(1–2), 1–53; discussion 54–55 (2002).
    • 69 Ellenbogen R, Abdulrauf S, Sekhar L. Principles Of Neurological Surgery. Elsevier Press, Seattle, WA. (2012).
    • 70 Amin-Hanjani S, Ogilvy CS, Ojemann RG, Crowell RM. Risks of surgical management for cavernous malformations of the nervous system. Neurosurgery 42(6), 1220–1227; discussion 1227–1228 (1998).
    • 71 Moultrie F, Horne MA, Josephson CB et al. Outcome after surgical or conservative management of cerebral cavernous malformations. Neurology 83(7), 582–589 (2014).
    • 72 Dalyai RT, Ghobrial G, Awad I et al. Management of incidental cavernous malformations: a review. Neurosurg. Focus 31(6), E5 (2011).
    • 73 Golden M, Saeidi S, Liem B, Marchand E, Morrison L, Hart B. Sensitivity of patients with familial cerebral cavernous malformations to therapeutic radiation. J. Med. Imaging Radiat. Oncol. 59(1), 134–136 (2015).
    • 74 Pham M, Gross BA, Bendok BR, Awad IA, Batjer HH. Radiosurgery for angiographically occult vascular malformations. Neurosurg. Focus 26(5), E16 (2009).
    • 75 Borikova AL, Dibble CF, Sciaky N et al. Rho kinase inhibition rescues the endothelial cell cerebral cavernous malformation phenotype. J. Biol. Chem. 285(16), 11760–11764 (2010).
    • 76 Crose LE, Hilder TL, Sciaky N, Johnson GL. Cerebral cavernous malformation 2 protein promotes smad ubiquitin regulatory factor 1-mediated Rhoa degradation in endothelial cells. J. Biol. Chem. 284(20), 13301–13305 (2009).
    • 77 Chen W, Mao K, Liu Z, Dinh-Xuan AT. The role of the Rhoa/Rho kinase pathway in angiogenesis and its potential value in prostate cancer (review). Oncol. Lett. 8(5), 1907–1911 (2014).
    • 78 Van Nieuw Amerongen GP, Koolwijk P, Versteilen A, Van Hinsbergh VW. Involvement of Rhoa/Rho kinase signaling in vegf-induced endothelial cell migration and angiogenesis in vitro. Arterioscler. Thromb. Vasc. Biol. 23(2), 211–217 (2003).
    • 79 Mei Y, Liao JK. Rho kinase and angiogenesis. Immunol. Endocrine Metabolic Agents in Med. Chem. 14(3), 14–28 (2014).
    • 80 Glading A, Han J, Stockton RA, Ginsberg MH. Krit-1/ccm1 is a rap1 effector that regulates endothelial cell cell junctions. J. Cell Sci. 179(2), 247–254 (2007).
    • 81 Cooper GM. The Cell: A Molecular Approach. Sinauer associates, Sunderland, MA. (2000).
    • 82 Dudek SM, Garcia JG. Cytoskeletal regulation of pulmonary vascular permeability. J. Appl. Physiol. 91(4), 1487–1500 (2001).
    • 83 Garcia JG, Schaphorst KL. Regulation of endothelial cell gap formation and paracellular permeability. J. Investig. Med. 43(2), 117–126 (1995).
    • 84 Kluger MS. 6. Vascular endothelial cell adhesion and signaling during leukocyte recruitment. Adv. Dermatol. 20, 163–164 (2004).
    • 85 Baumer Y, Burger S, Curry F, Golenhofen N, Drenckhahn D, Waschke J. Differential role of Rho gtpases in endothelial barrier regulation dependent on endothelial cell origin. Histochem. Cell Biol. 129(2), 179–191 (2008).
    • 86 Terry S, Nie M, Matter K, Balda MS. Rho signaling and tight junction functions. Physiology 25(1), 16–26 (2010).
    • 87 Wojciak-Stothard B, Potempa S, Eichholtz T, Ridley AJ. Rho and rac but not cdc42 regulate endothelial cell permeability. J. Cell Sci. 114(Pt 7), 1343–1355 (2001).
    • 88 Smith AL, Dohn MR, Brown MV, Reynolds AB. Association of Rho-associated protein kinase 1 with e-cadherin complexes is mediated by p120-catenin. Mol. Biol. Cell 23(1), 99–110 (2012).
    • 89 Mcdonald DA, Shi C, Shenkar R et al. Lesions from patients with sporadic cerebral cavernous malformations harbor somatic mutations in the ccm genes: evidence for a common biochemical pathway for ccm pathogenesis. Hum. Mol. Genet. 23(16), 4357–4370 (2014).
    • 90 Mcdonald DA, Shi C, Shenkar R et al. Fasudil decreases lesion burden in a murine model of cerebral cavernous malformation disease. Stroke 43(2), 571–574 (2012).
    • 91 Humphrey JD, Taylor CA. Intracranial and abdominal aortic aneurysms: Similarities, differences, and need for a new class of computational models. Annu. Rev. Biomed. Eng. 10, 221–246 (2008).
    • 92 Sekhar LN, Heros RC. Origin, growth, and rupture of saccular aneurysms: A review. Neurosurgery 8(2), 248–260 (1981).
    • 93 Stehbens WE. Histopathology of cerebral aneurysms. Arch. Neurol. 8, 272–285 (1963).
    • 94 Scanarini M, Mingrino S, Giordano R, Baroni A. Histological and ultrastructural study of intracranial saccular aneurysmal wall. Acta Neurochir. (Wien.) 43(3–4), 171–182 (1978).
    • 95 Humphrey J, Taylor C. Intracranial and abdominal aortic aneurysms: Similarities, differences, and need for a new class of computational models. Annu. Rev. Biomed. Eng. 10, 221 (2008).
    • 96 Crompton MR. The pathology of ruptured middle-cerebral aneurysms with special reference to the differences between the sexes. Lancet 2(7253), 421–425 (1962).
    • 97 Qureshi AI, Suarez JI, Parekh PD et al. Risk factors for multiple intracranial aneurysms. Neurosurgery 43(1), 22–26; discussion 26–27 (1998).
    • 98 Rinkel GJ, Djibuti M, Algra A, Van Gijn J. Prevalence and risk of rupture of intracranial aneurysms: a systematic review. Stroke 29(1), 251–256 (1998).
    • 99 Kurki MI, Häkkinen S-K, Frösen J et al. Upregulated signaling pathways in ruptured human saccular intracranial aneurysm wall: an emerging regulative role of toll-like receptor signaling and nuclear factor-κb, hypoxia-inducible factor-1a, and ets transcription factors. Neurosurgery 68(6), 1667–1676 (2011).
    • 100 Johnston SC, Higashida RT, Barrow DL et al. Recommendations for the endovascular treatment of intracranial aneurysms: a statement for healthcare professionals from the committee on cerebrovascular imaging of the american heart association council on cardiovascular radiology. Stroke 33(10), 2536–2544 (2002).
    • 101 Alawi A, Edgell RC, Elbabaa SK et al. Treatment of cerebral aneurysms in children: analysis of the kids' inpatient database. J. Neurosurg. Pediatr. 14(1), 23–30 (2014).
    • 102 Taha MM, Nakahara I, Higashi T et al. Endovascular embolization vs surgical clipping in treatment of cerebral aneurysms: morbidity and mortality with short-term outcome. Surg. Neurol. 66(3), 277–284; discussion 284 (2006).
    • 103 Mackey J, Brown RD Jr, Moomaw CJ et al. Familial intracranial aneurysms: is anatomic vulnerability heritable? Stroke 44(1), 38–42 (2013).
    • 104 Broderick JP, Brown RD Jr, Sauerbeck L et al. Greater rupture risk for familial as compared with sporadic unruptured intracranial aneurysms. Stroke 40(6), 1952–1957 (2009).
    • 105 Stehbens WE. Pathology and pathogenesis of intracranial berry aneurysms. Neurol. Res. 12(1), 29–34 (1990).
    • 106 Finlay HM, Whittaker P, Canham PB. Collagen organization in the branching region of human brain arteries. Stroke 29(8), 1595–1601 (1998).
    • 107 Inci S, Spetzler RF. Intracranial aneurysms and arterial hypertension: a review and hypothesis. Surg. Neurol. 53(6), 530–540; discussion 540–532 (2000).
    • 108 Eldawoody H, Shimizu H, Kimura N et al. Fasudil, a Rho-kinase inhibitor, attenuates induction and progression of cerebral aneurysms: Experimental study in rats using vascular corrosion casts. Neurosci. Lett. 470(1), 76–80 (2010).
    • 109 Hashimoto N, Hadna H, Nagata I, Hazama F. (Experimental inducement of saccular cerebral aneuryms in rats [author's transl]). No Shinkei Geka 8(1), 31–34 (1980).
    • 110 Hashimoto N, Kim C, Kikuchi H, Kojima M, Kang Y, Hazama F. Experimental induction of cerebral aneurysms in monkeys. J. Neurosurg. 67(6), 903–905 (1987).
    • 111 Handa H, Hashimoto N, Nagata I, Hazama F. Saccular cerebral aneurysms in rats: a newly developed animal model of the disease. Stroke 14(6), 857–866 (1983).
    • 112 Nagata I, Handa H, Hashimoto N, Hazama F. Experimentally induced cerebral aneurysms in rats: Part VI. Hypertension. Surg. Neurol. 14(6), 477–479 (1980).
    • 113 Kondo S, Hashimoto N, Kikuchi H, Hazama F, Nagata I, Kataoka H. Cerebral aneurysms arising at nonbranching sites. An experimental study. Stroke 28(2), 398–403; discussion 403–394 (1997).
    • 114 De La Monte SM, Moore GW, Monk MA, Hutchins GM. Risk factors for the development and rupture of intracranial berry aneurysms. Am. J. Med. 78(6 Pt 1), 957–964 (1985).
    • 115 Mukai Y, Shimokawa H, Matoba T et al. Involvement of Rho-kinase in hypertensive vascular disease: a novel therapeutic target in hypertension. FASEB J. 15(6), 1062–1064 (2001).
    • 116 Uehata M, Ishizaki T, Satoh H et al. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature 389(6654), 990–994 (1997).
    • 117 Heissler SM, Manstein DJ. Nonmuscle myosin-2: Mix and match. Cell. Mol. Life Sci. 70(1), 1–21 (2013).
    • 118 Kolluru GK, Majumder S, Chatterjee S. Rho-kinase as a therapeutic target in vascular diseases: striking nitric oxide signaling. Nitric Oxide 43, 45–54 (2014).
    • 119 Peterson EC, Wang Z, Britz G. Regulation of cerebral blood flow. Int. J. Vasc. Med. 2011 823525 (2011).
    • 120 Willie CK, Tzeng YC, Fisher JA, Ainslie PN. Integrative regulation of human brain blood flow. J. Physiol. 592(Pt 5), 841–859 (2014).
    • 121 Paulson OB, Strandgaard S, Edvinsson L. Cerebral autoregulation. Cerebrovasc. Brain Metab. Rev. 2(2), 161–192 (1990).
    • 122 Tan CO, Hamner JW, Taylor JA. The role of myogenic mechanisms in human cerebrovascular regulation. J. Physiol. 591(Pt 20), 5095–5105 (2013).
    • 123 Gonzalez R, Fernandez-Alfonso MS, Rodriguez-Martinez MA et al. Pressure-induced contraction of the juxtamedullary afferent arterioles in spontaneously hypertensive rats. Gen. Pharmacol. 25(2), 333–339 (1994).
    • 124 Harder DR, Roman RJ, Gebremedhin D, Birks EK, Lange AR. A common pathway for regulation of nutritive blood flow to the brain: arterial muscle membrane potential and cytochrome p450 metabolites. Acta Physiol. Scand. 164(4), 527–532 (1998).
    • 125 Masumoto N, Tanabe Y, Saito M, Nakayama K. Attenuation of pressure-induced myogenic contraction and tyrosine phosphorylation by fasudil, a cerebral vasodilator, in rat cerebral artery. Br. J. Pharmacol. 130(2), 219–230 (2000).
    • 126 Gokina NI, Park KM, Mcelroy-Yaggy K, Osol G. Effects of Rho kinase inhibition on cerebral artery myogenic tone and reactivity. J. Appl. Physiol. 98(5), 1940–1948 (2005).
    • 127 Tanweer O, Wilson T, Metaxa E, Riina H, Meng H. E-016 a comparative review of the hemodynamics and pathogenesis of cerebral and abdominal aortic aneurysms: lessons to learn from each other. J. Neurointerv. Surg. 6(Suppl. 1), A45 (2014).
    • 128 Stehbens WE. Etiology of intracranial berry aneurysms. J. Neurosurg. 70(6), 823–831 (1989).
    • 129 Langille BL. Arterial remodeling: relation to hemodynamics. Can. J. Physiol. Pharmacol. 74(7), 834–841 (1996).
    • 130 Cebral JR, Vazquez M, Sforza DM et al. Analysis of hemodynamics and wall mechanics at sites of cerebral aneurysm rupture. J. Neurointerv. Surg. doi:10.1136/neurintsurg-2014-011247 (2014)(Epub ahead of print).
    • 131 Ellegala DB, Day AL. Ruptured cerebral aneurysms. N. Engl. J. Med. 352(2), 121–124 (2005).
    • 132 Hashimoto T, Meng H, Young WL. Intracranial aneurysms: links among inflammation, hemodynamics and vascular remodeling. Neurol. Res. 28(4), 372–380 (2006).
    • 133 Strother CM, Graves VB, Rappe A. Aneurysm hemodynamics: an experimental study. AJNR Am. J. Neuroradiol. 13(4), 1089–1095 (1992).
    • 134 Xiang J, Yu J, Choi H et al. Rupture resemblance score (rrs): toward risk stratification of unruptured intracranial aneurysms using hemodynamic-morphological discriminants. J. Neurointerv. Surg. (2014).
    • 135 Davies PF. Flow-mediated endothelial mechanotransduction. Physiol. Rev. 75(3), 519–560 (1995).
    • 136 Shay-Salit A, Shushy M, Wolfovitz E et al. Vegf receptor 2 and the adherens junction as a mechanical transducer in vascular endothelial cells. Proc. Natl Acad. Sci. USA 99(14), 9462–9467 (2002).
    • 137 Kano Y, Katoh K, Fujiwara K. Lateral zone of cell-cell adhesion as the major fluid shear stress-related signal transduction site. Circ. Res. 86(4), 425–433 (2000).
    • 138 Li S, Chen BP, Azuma N et al. Distinct roles for the small gtpases cdc42 and Rho in endothelial responses to shear stress. J. Clin. Invest. 103(8), 1141–1150 (1999).
    • 139 Tzima E. Role of small gtpases in endothelial cytoskeletal dynamics and the shear stress response. Circ. Res. 98(2), 176–185 (2006).
    • 140 Van Der Meel R, Symons MH, Kudernatsch R et al. The vegf/Rho gtpase signalling pathway: a promising target for anti-angiogenic/anti-invasion therapy. Drug Discov. Today 16(5–6), 219–228 (2011).
    • 141 Hoang MV, Whelan MC, Senger DR. Rho activity critically and selectively regulates endothelial cell organization during angiogenesis. Proc. Natl Acad. Sci. USA 101(7), 1874–1879 (2004).
    • 142 Li F, Xia W, Li A, Zhao C, Sun R. Long-term inhibition of Rho kinase with fasudil attenuates high flow induced pulmonary artery remodeling in rats. Pharmacol. Res. 55(1), 64–71 (2007).
    • 143 Yasuno K, Bilguvar K, Bijlenga P et al. Genome-wide association study of intracranial aneurysm identifies three new risk loci. Nat. Genet. 42(5), 420–425 (2010).
    • 144 Takahashi M, Ishida T, Traub O, Corson MA, Berk BC. Mechanotransduction in endothelial cells: temporal signaling events in response to shear stress. J. Vasc. Res. 34(3), 212–219 (1997).
    • 145 Chyatte D, Bruno G, Desai S, Todor DR. Inflammation and intracranial aneurysms. Neurosurgery 45(5), 1137–1146; discussion 1146–1137 (1999).
    • 146 Kataoka K, Taneda M, Asai T, Kinoshita A, Ito M, Kuroda R. Structural fragility and inflammatory response of ruptured cerebral aneurysms. A comparative study between ruptured and unruptured cerebral aneurysms. Stroke 30(7), 1396–1401 (1999).
    • 147 Frosen J, Piippo A, Paetau A et al. Remodeling of saccular cerebral artery aneurysm wall is associated with rupture: histological analysis of 24 unruptured and 42 ruptured cases. Stroke 35(10), 2287–2293 (2004).
    • 148 Millan J, Ridley AJ. Rho gtpases and leucocyte-induced endothelial remodelling. Biochem. J. 385(Pt 2), 329–337 (2005).
    • 149 Newman-Tancredi A, Cussac D, Marini L, Millan MJ. Antibody capture assay reveals bell-shaped concentration-response isotherms for h5-ht1a receptor-mediated gαi3activation: conformational selection by high-efficacy agonists, and relationship to trafficking of receptor signaling. Molec. Pharm. 62(3), 590 (2002).
    • 150 Strey A, Janning A, Barth H, Gerke V. Endothelial Rho signaling is required for monocyte transendothelial migration. FEBS Lett. 517(1), 261–266 (2002).
    • 151 Zhang W, Zhan X, Gao M et al. Self-assembling peptide nanofiber scaffold enhanced with Rhoa inhibitor ct04 improves axonal regrowth in the transected spinal cord. J. Nanomater. 2012 54 (2012).
    • 152 Wang YX, Martin-Mcnulty B, Da Cunha V et al. Fasudil, a Rho-kinase inhibitor, attenuates angiotensin ii-induced abdominal aortic aneurysm in apolipoprotein e-deficient mice by inhibiting apoptosis and proteolysis. Circulation 111(17), 2219–2226 (2005).
    • 153 Tsai SH, Huang PH, Peng YJ et al. Zoledronate attenuates angiotensin ii-induced abdominal aortic aneurysm through inactivation of Rho/rock-dependent jnk and nf-kappab pathway. Cardiovasc. Res. 100(3), 501–510 (2013).
    • 154 Zhao J, Zhou D, Guo J et al. Efficacy and safety of fasudil in patients with subarachnoid hemorrhage: final results of a randomized trial of fasudil versus nimodipine. Neurol. Med. Chir. (Tokyo) 51(10), 679–683 (2011).
    • 155 Shibuya M, Suzuki Y, Sugita K et al. Effect of at877 on cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Results of a prospective placebo-controlled double-blind trial. J. Neurosurg. 76(4), 571–577 (1992).
    • 156 Suzuki Y, Shibuya M, Satoh S, Sugimoto Y, Takakura K. A postmarketing surveillance study of fasudil treatment after aneurysmal subarachnoid hemorrhage. Surg. Neurol. 68(2), 126–131; discussion 131–122 (2007).
    • 157 Fehlings M, Theodore N, Harrop J et al. A phase i/iia clinical trial of a recombinant Rho protein antagonist in acute spinal cord injury. J. Neurotrauma 28, 787–796 (2011).
    • 158 Feng Y, Lograsso PV. Rho kinase inhibitors: a patent review (2012 -2013). Expert Opin. Ther. Pat. 24(3), 295–307 (2014).
    • 159 Leysen D, Defert O, Boland S, Al. E. Novel rock inhibitors. Wo 2012146724. (2012).
    • 160 Allen J, Boland S, Bourin A, Al. E. Novel soft rock inhibitors. Wo 2013030366. (2013).
    • 161 Allen J, Boland S, Bourin A, Al. E. Novel rock inhibitors. Wo 2013030365. (2013).
    • 162 Allen J, Boland S, Bourin A, Al. E. Biphenylcarboxamides as rock kinase inhibitors. Wo 2013030367. (2013).
    • 163 Guan R, Xu X, Chen M et al. Advances in the studies of roles of Rho/Rho-kinase in diseases and the development of its inhibitors. Eur. J. Med. Chem. 70, 613–622 (2013).
    • 164 Hou T, Yu H, Shen M, Al. E. Application of compound in preparing anti-tumor medicament. Cn102697782. (2012).
    • 165 Hou T, Yu H, Shen M, Al. E. Application of 3–4-(sulfonyl)benzene] urea compound to preparation of antitumor medicament. Cn102327275. (2012).
    • 166 Hou T, Yu H, Shen M, Al. E. 4,7-dihydrotetrazole[1,5-a]pyrimidine derivative and application thereof to preparation of antitumor medicine. Cn102432612. (2012).
    • 167 Cook BN, Kowalski J, Li X, Al. E. N-cyclyl-3-(cyclylcarbonylaminomethyl) benzamide derivatives as Rho kinase inhibitors. Wo 2012006203. (2012).
    • 168 Zhang JY, Dong HS, Oqani RK, Lin T, Kang JW, Jin DI. Distinct roles of rock1 and rock2 during development of porcine preimplantation embryos. Reproduction 148(1), 99–107 (2014).
    • 169 Montalvo J, Spencer C, Hackathorn A et al. Rock1 & 2 perform overlapping and unique roles in angiogenesis and angiosarcoma tumor progression. Curr. Mol. Med. 13(1), 205–219 (2013).
    • 170 Shi J, Wu X, Surma M et al. Distinct roles for rock1 and rock2 in the regulation of cell detachment. Cell Death Dis. 4, e483 (2013).
    • 171 Mertsch S, Thanos S. Opposing signaling of rock1 and rock2 determines the switching of substrate specificity and the mode of migration of glioblastoma cells. Mol. Neurobiol. 49(2), 900–915 (2014).
    • 172 Mckerracher L, Thouin E, Lubell W, Al. E. 4-substituted piperidine derivatives. Wo03042174. (2005).
    • 173 Liu PY, Liu YW, Lin LJ, Chen JH, Liao JK. Evidence for statin pleiotropy in humans: differential effects of statins and ezetimibe on Rho-associated coiled-coil containing protein kinase activity, endothelial function, and inflammation. Circulation 119(1), 131–138 (2009).
    • 174 Nohria A, Prsic A, Liu PY et al. Statins inhibit Rho kinase activity in patients with atherosclerosis. Atherosclerosis 205(2), 517–521 (2009).
    • 175 Li DY, Whitehead KJ. Evaluating strategies for the treatment of cerebral cavernous malformations. Stroke 41(10 Suppl.), S92–S94 (2010).
    • 176 Patterson C. Torturing a blood vessel. Nature medicine 15(2), 137–138 (2009).
    • 177 Whitehead KJ, Chan AC, Navankasattusas S et al. The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho gtpases. Nat. Med. 15(2), 177–184 (2009).
    • 178 Yoshimura Y, Murakami Y, Saitoh M et al. Statin use and risk of cerebral aneurysm rupture: a hospital-based case-control study in Japan. J. Stroke Cerebrovasc. Dis. 23(2), 343–348 (2014).
    • 179 Eisa-Beygi S, Wen XY, Macdonald RL. A call for rigorous study of statins in resolution of cerebral cavernous malformation pathology. Stroke 45(6), 1859–1861 (2014).