Abstract
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 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 . Intracranial aneurysms. N. Engl. J. Med. 336(1), 28–40 (1997).
- 3 . Emerging clinical imaging techniques for cerebral cavernous malformations: a systematic review. Neurosurg. Focus 29(3), E6 (2010).
- 4 . Diagnosis and treatment of vascular malformations of the brain. Curr. Treat. Options Neurol. 16(1), 279 (2014).
- 5 Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 362(9378), 103–110 (2003).
- 6 . Rho kinases in cardiovascular physiology and pathophysiology. Circ. Res. 98(3), 322–334 (2006).
- 7 . Gtp-binding proteins and the regulation of the actin cytoskeleton. Ann. Rev. Cell Biol. 10, 31–54 (1996).
- 8 . The blood–brain barrier in health and chronic neurodegenerative disorders. Neuron 57(2), 178–201 (2008).
- 9 . Pathophysiology of the neurovascular unit: disease cause or consequence? J. Cereb. Blood Flow Metab. 32(7), 1207–1221 (2012).
- 10 Engaging neuroscience to advance translational research in brain barrier biology. Nat. Rev. Neurosci. 12(3), 169–182 (2011).
- 11 . Brain endothelial cell-cell junctions: how to “open” the blood brain barrier. Curr. Neuropharmacol. 6(3), 179–192 (2008).
- 12 . 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 . Adherens and tight junctions: Structure, function and connections to the actin cytoskeleton. Biochim. Biophys. Acta 1778(3), 660–669 (2008).
- 14 Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J. Cell Biol. 153(3), 543–554 (2001).
- 15 . N‐cadherin mediates pericytic‐endothelial interaction during brain angiogenesis in the chicken. Dev. Dyn. 218(3), 472–479 (2000).
- 16 . Pericytes: pluripotent cells of the blood–brain barrier. Curr. Pharm. Design 14(16), 1581–1593 (2008).
- 17 . Cellular mechanisms of CNS pericytes. Brain Res. Bull. 51(5), 363–369 (2000).
- 18 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 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 . Rho kinase, a promising drug target for neurological disorders. Nat. Rev. Drug Discov. 4(5), 387–398 (2005).
- 21 . 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 Selective rock2 inhibition in focal cerebral ischemia. Ann. Clin. Transl. Neurol. 1(1), 2–14 (2014).
- 23 . Rocks: multifunctional kinases in cell behaviour. Nat. Rev. Mol. Cell Biol. 4(6), 446–456 (2003).
- 24 Rho-kinase: regulation, (dys)function, and inhibition. Biol. Chem. 394(11), 1399–1410 (2013).
- 25 Rho-associated kinase directly induces smooth muscle contraction through myosin light chain phosphorylation. J. Biol. Chem. 272(19), 12257–12260 (1997).
- 26 Phosphorylation of myosin-binding subunit (mbs) of myosin phosphatase by Rho-kinase in vivo. J. Cell Sci. 147(5), 1023–1038 (1999).
- 27 . 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 . Rho-kinase: Important new therapeutic target in cardiovascular diseases. Am. J. Physiol. Heart Circ. Physiol. 301(2), H287–H296 (2011).
- 29 . Rho-kinase-mediated contraction of isolated stress fibers. J. Cell Sci. 153(3), 569–584 (2001).
- 30 Phosphorylation of cpi-17, an inhibitory phosphoprotein of smooth muscle myosin phosphatase, by Rho-kinase. FEBS Lett. 475(3), 197–200 (2000).
- 31 . Rho signaling and tight junction functions. Physiology (Bethesda) 25(1), 16–26 (2010).
- 32 . 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 Phosphorylation of claudin-5 and occludin by Rho kinase in brain endothelial cells. Am. J. Pathol. 172(2), 521–533 (2008).
- 34 . 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 . Rock and dia have opposing effects on adherens junctions downstream of Rho. Nat. Cell Biol. 4(6), 408–415 (2002).
- 36 . 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 Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature 389(6654), 990–994 (1997).
- 38 . Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. J. 351(Pt 1), 95–105 (2000).
- 39 Development of specific Rho-kinase inhibitors and their clinical application. Biochim. Biophys. Acta 1754(1–2), 245–252 (2005).
- 40 . Signaling through Rho gtpase pathway as viable drug target. Curr. Med. Chem. 16(11), 1355–1365 (2009).
- 41 . Rho kinases in cardiovascular physiology and pathophysiology. Circ. Res. 98(3), 322–334 (2006).
- 42 . Rho-kinase: important new therapeutic target in cardiovascular diseases. Am. J. Physiol. Heart Circ. Physiol. 301(2), H287–296 (2011).
- 43 . 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 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 Inactivation of the small gtp-binding protein Rho promotes cns axon regeneration. J. Neurosci 19, 7537–7547 (1999).
- 46 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 Selective rock2 inhibition in focal cerebral ischemia. Ann. Clin. Transl. Neurol. 1(1), 2–14 (2014).
- 48 Involvement of Rho-kinase in hypertensive vascular disease: a novel therapeutic target in hypertension. FASEB J. 15(6), 1062–1064 (2001).
- 49 . 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 . Genetics of cerebral cavernous malformations. Curr. Neurol. Neurosci. Rep. 5(5), 391–396 (2005).
- 51 Natural history and imaging prevalence of cavernous malformations in children and young adults. J. Neurosurg. Pediatr. 9(2), 198–205 (2012).
- 52 . An analysis of the natural history of cavernous angiomas. J. Neurosurg. 75(5), 702–708 (1991).
- 53 . Natural history of the cavernous angioma. J. Neurosurg. 75(5), 709–714 (1991).
- 54 . Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity. J. Exp. Med. 207(4), 881–896 (2010).
- 55 . Cerebral Cavernous Malformations, Familial. University of Washington, Seattle WA. (2003).
- 56 . 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 The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho gtpases. Nat. Med. 15(2), 177–184 (2009).
- 58 Ccm1 and ccm2 protein interactions in cell signaling: implications for cerebral cavernous malformations pathogenesis. Hum. Mol. Genet. 14(17), 2521–2531 (2005).
- 59 Proteomic identification of the cerebral cavernous malformation signaling complex. J. Proteome Res. 6(11), 4343–4355 (2007).
- 60 . Biology of vascular malformations of the brain NWC. Biology of vascular malformations of the brain. Stroke 40(12), e694–702 (2009).
- 61 . Recent insights into cerebral cavernous malformations: a complex jigsaw puzzle under construction. FEBS J. 277(5), 1084–1096 (2010).
- 62 Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am. J. Hum. Genet. 76(1), 42–51 (2005).
- 63 Clinical features of cerebral cavernous malformations patients with krit1 mutations. Ann. Neurol. 55(2), 213–220 (2004).
- 64 . Ultrastructural pathological features of cerebrovascular malformations: a preliminary report. Neurosurgery 46(6), 1454–1459 (2000).
- 65 . 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 . Ultrastructural characteristics of hemorrhagic, nonhemorrhagic, and recurrent cavernous malformations. J. Neurosurg. 103(5), 903–909 (2005).
- 67 . Ultrastructural analysis of vascular features in cerebral cavernous malformations. Clin. Neurol. Neurosurg. 115(4), 438–444 (2013).
- 68 . 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 . Principles Of Neurological Surgery. Elsevier Press, Seattle, WA. (2012).
- 70 . Risks of surgical management for cavernous malformations of the nervous system. Neurosurgery 42(6), 1220–1227; discussion 1227–1228 (1998).
- 71 Outcome after surgical or conservative management of cerebral cavernous malformations. Neurology 83(7), 582–589 (2014).
- 72 Management of incidental cavernous malformations: a review. Neurosurg. Focus 31(6), E5 (2011).
- 73 . Sensitivity of patients with familial cerebral cavernous malformations to therapeutic radiation. J. Med. Imaging Radiat. Oncol. 59(1), 134–136 (2015).
- 74 . Radiosurgery for angiographically occult vascular malformations. Neurosurg. Focus 26(5), E16 (2009).
- 75 Rho kinase inhibition rescues the endothelial cell cerebral cavernous malformation phenotype. J. Biol. Chem. 285(16), 11760–11764 (2010).
- 76 . 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 . 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 . 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 . Rho kinase and angiogenesis. Immunol. Endocrine Metabolic Agents in Med. Chem. 14(3), 14–28 (2014).
- 80 . Krit-1/ccm1 is a rap1 effector that regulates endothelial cell cell junctions. J. Cell Sci. 179(2), 247–254 (2007).
- 81 . The Cell: A Molecular Approach. Sinauer associates, Sunderland, MA. (2000).
- 82 . Cytoskeletal regulation of pulmonary vascular permeability. J. Appl. Physiol. 91(4), 1487–1500 (2001).
- 83 . Regulation of endothelial cell gap formation and paracellular permeability. J. Investig. Med. 43(2), 117–126 (1995).
- 84 . 6. Vascular endothelial cell adhesion and signaling during leukocyte recruitment. Adv. Dermatol. 20, 163–164 (2004).
- 85 . Differential role of Rho gtpases in endothelial barrier regulation dependent on endothelial cell origin. Histochem. Cell Biol. 129(2), 179–191 (2008).
- 86 . Rho signaling and tight junction functions. Physiology 25(1), 16–26 (2010).
- 87 . Rho and rac but not cdc42 regulate endothelial cell permeability. J. Cell Sci. 114(Pt 7), 1343–1355 (2001).
- 88 . 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 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 Fasudil decreases lesion burden in a murine model of cerebral cavernous malformation disease. Stroke 43(2), 571–574 (2012).
- 91 . 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 . Origin, growth, and rupture of saccular aneurysms: A review. Neurosurgery 8(2), 248–260 (1981).
- 93 . Histopathology of cerebral aneurysms. Arch. Neurol. 8, 272–285 (1963).
- 94 . Histological and ultrastructural study of intracranial saccular aneurysmal wall. Acta Neurochir. (Wien.) 43(3–4), 171–182 (1978).
- 95 . Intracranial and abdominal aortic aneurysms: Similarities, differences, and need for a new class of computational models. Annu. Rev. Biomed. Eng. 10, 221 (2008).
- 96 . The pathology of ruptured middle-cerebral aneurysms with special reference to the differences between the sexes. Lancet 2(7253), 421–425 (1962).
- 97 Risk factors for multiple intracranial aneurysms. Neurosurgery 43(1), 22–26; discussion 26–27 (1998).
- 98 . Prevalence and risk of rupture of intracranial aneurysms: a systematic review. Stroke 29(1), 251–256 (1998).
- 99 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 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 Treatment of cerebral aneurysms in children: analysis of the kids' inpatient database. J. Neurosurg. Pediatr. 14(1), 23–30 (2014).
- 102 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 Familial intracranial aneurysms: is anatomic vulnerability heritable? Stroke 44(1), 38–42 (2013).
- 104 Greater rupture risk for familial as compared with sporadic unruptured intracranial aneurysms. Stroke 40(6), 1952–1957 (2009).
- 105 . Pathology and pathogenesis of intracranial berry aneurysms. Neurol. Res. 12(1), 29–34 (1990).
- 106 . Collagen organization in the branching region of human brain arteries. Stroke 29(8), 1595–1601 (1998).
- 107 . Intracranial aneurysms and arterial hypertension: a review and hypothesis. Surg. Neurol. 53(6), 530–540; discussion 540–532 (2000).
- 108 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 . (Experimental inducement of saccular cerebral aneuryms in rats [author's transl]). No Shinkei Geka 8(1), 31–34 (1980).
- 110 . Experimental induction of cerebral aneurysms in monkeys. J. Neurosurg. 67(6), 903–905 (1987).
- 111 . Saccular cerebral aneurysms in rats: a newly developed animal model of the disease. Stroke 14(6), 857–866 (1983).
- 112 . Experimentally induced cerebral aneurysms in rats: Part VI. Hypertension. Surg. Neurol. 14(6), 477–479 (1980).
- 113 . Cerebral aneurysms arising at nonbranching sites. An experimental study. Stroke 28(2), 398–403; discussion 403–394 (1997).
- 114 . Risk factors for the development and rupture of intracranial berry aneurysms. Am. J. Med. 78(6 Pt 1), 957–964 (1985).
- 115 Involvement of Rho-kinase in hypertensive vascular disease: a novel therapeutic target in hypertension. FASEB J. 15(6), 1062–1064 (2001).
- 116 Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature 389(6654), 990–994 (1997).
- 117 . Nonmuscle myosin-2: Mix and match. Cell. Mol. Life Sci. 70(1), 1–21 (2013).
- 118 . Rho-kinase as a therapeutic target in vascular diseases: striking nitric oxide signaling. Nitric Oxide 43, 45–54 (2014).
- 119 . Regulation of cerebral blood flow. Int. J. Vasc. Med. 2011 823525 (2011).
- 120 . Integrative regulation of human brain blood flow. J. Physiol. 592(Pt 5), 841–859 (2014).
- 121 . Cerebral autoregulation. Cerebrovasc. Brain Metab. Rev. 2(2), 161–192 (1990).
- 122 . The role of myogenic mechanisms in human cerebrovascular regulation. J. Physiol. 591(Pt 20), 5095–5105 (2013).
- 123 Pressure-induced contraction of the juxtamedullary afferent arterioles in spontaneously hypertensive rats. Gen. Pharmacol. 25(2), 333–339 (1994).
- 124 . 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 . 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 . Effects of Rho kinase inhibition on cerebral artery myogenic tone and reactivity. J. Appl. Physiol. 98(5), 1940–1948 (2005).
- 127 . 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 . Etiology of intracranial berry aneurysms. J. Neurosurg. 70(6), 823–831 (1989).
- 129 . Arterial remodeling: relation to hemodynamics. Can. J. Physiol. Pharmacol. 74(7), 834–841 (1996).
- 130 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 . Ruptured cerebral aneurysms. N. Engl. J. Med. 352(2), 121–124 (2005).
- 132 . Intracranial aneurysms: links among inflammation, hemodynamics and vascular remodeling. Neurol. Res. 28(4), 372–380 (2006).
- 133 . Aneurysm hemodynamics: an experimental study. AJNR Am. J. Neuroradiol. 13(4), 1089–1095 (1992).
- 134 Rupture resemblance score (rrs): toward risk stratification of unruptured intracranial aneurysms using hemodynamic-morphological discriminants. J. Neurointerv. Surg. (2014).
- 135 . Flow-mediated endothelial mechanotransduction. Physiol. Rev. 75(3), 519–560 (1995).
- 136 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 . Lateral zone of cell-cell adhesion as the major fluid shear stress-related signal transduction site. Circ. Res. 86(4), 425–433 (2000).
- 138 Distinct roles for the small gtpases cdc42 and Rho in endothelial responses to shear stress. J. Clin. Invest. 103(8), 1141–1150 (1999).
- 139 . Role of small gtpases in endothelial cytoskeletal dynamics and the shear stress response. Circ. Res. 98(2), 176–185 (2006).
- 140 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 . Rho activity critically and selectively regulates endothelial cell organization during angiogenesis. Proc. Natl Acad. Sci. USA 101(7), 1874–1879 (2004).
- 142 . 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 Genome-wide association study of intracranial aneurysm identifies three new risk loci. Nat. Genet. 42(5), 420–425 (2010).
- 144 . Mechanotransduction in endothelial cells: temporal signaling events in response to shear stress. J. Vasc. Res. 34(3), 212–219 (1997).
- 145 . Inflammation and intracranial aneurysms. Neurosurgery 45(5), 1137–1146; discussion 1146–1137 (1999).
- 146 . 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 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 . Rho gtpases and leucocyte-induced endothelial remodelling. Biochem. J. 385(Pt 2), 329–337 (2005).
- 149 . 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 . Endothelial Rho signaling is required for monocyte transendothelial migration. FEBS Lett. 517(1), 261–266 (2002).
- 151 Self-assembling peptide nanofiber scaffold enhanced with Rhoa inhibitor ct04 improves axonal regrowth in the transected spinal cord. J. Nanomater. 2012 54 (2012).
- 152 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 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 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 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 . A postmarketing surveillance study of fasudil treatment after aneurysmal subarachnoid hemorrhage. Surg. Neurol. 68(2), 126–131; discussion 131–122 (2007).
- 157 A phase i/iia clinical trial of a recombinant Rho protein antagonist in acute spinal cord injury. J. Neurotrauma 28, 787–796 (2011).
- 158 . Rho kinase inhibitors: a patent review (2012 -2013). Expert Opin. Ther. Pat. 24(3), 295–307 (2014).
- 159 . Novel rock inhibitors. Wo 2012146724. (2012).
- 160 . Novel soft rock inhibitors. Wo 2013030366. (2013).
- 161 . Novel rock inhibitors. Wo 2013030365. (2013).
- 162 . Biphenylcarboxamides as rock kinase inhibitors. Wo 2013030367. (2013).
- 163 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 . Application of compound in preparing anti-tumor medicament. Cn102697782. (2012).
- 165 . Application of 3–4-(sulfonyl)benzene] urea compound to preparation of antitumor medicament. Cn102327275. (2012).
- 166 . 4,7-dihydrotetrazole[1,5-a]pyrimidine derivative and application thereof to preparation of antitumor medicine. Cn102432612. (2012).
- 167 . N-cyclyl-3-(cyclylcarbonylaminomethyl) benzamide derivatives as Rho kinase inhibitors. Wo 2012006203. (2012).
- 168 . Distinct roles of rock1 and rock2 during development of porcine preimplantation embryos. Reproduction 148(1), 99–107 (2014).
- 169 Rock1 & 2 perform overlapping and unique roles in angiogenesis and angiosarcoma tumor progression. Curr. Mol. Med. 13(1), 205–219 (2013).
- 170 Distinct roles for rock1 and rock2 in the regulation of cell detachment. Cell Death Dis. 4, e483 (2013).
- 171 . 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 . 4-substituted piperidine derivatives. Wo03042174. (2005).
- 173 . 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 Statins inhibit Rho kinase activity in patients with atherosclerosis. Atherosclerosis 205(2), 517–521 (2009).
- 175 . Evaluating strategies for the treatment of cerebral cavernous malformations. Stroke 41(10 Suppl.), S92–S94 (2010).
- 176 . Torturing a blood vessel. Nature medicine 15(2), 137–138 (2009).
- 177 The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho gtpases. Nat. Med. 15(2), 177–184 (2009).
- 178 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 . A call for rigorous study of statins in resolution of cerebral cavernous malformation pathology. Stroke 45(6), 1859–1861 (2014).