Immunological factors, inflammation, or thrombosis may be associated with the development of obstruction/stenosis of the intracranial internal carotid arteries.
The presence of macrophages and T lymphocytes in the surface layer of the thickened intima suggest the possibility of chronic inflammation in SMC proliferation [20] .
Endothelial adhesion molecules, which include the intercellular adhesion molecule type 1 (ICAM-1), the vascular cell adhesion molecule type 1 (VCAM-1), and E-selectin, were previously reported to be increased in the CSF of MMD patients, which suggests the presence of ongoing immunological activation in the CNS [21] . Endothelial adhesion molecules are not only associated with inflammation but also activated by tissue ischemia and neovascularization [21] . Endothelial cells are the primary source of soluble ICAM-1 and VCAM-1 in various brain disorders. The elevated levels of these soluble adhesion molecules in the CSF may be the result of their increased expression in vascular endothelial cells [21] . However, the possibility of passive leakage from the systemic circulation or ongoing cerebral ischemia as a source of these adhesion molecules among this group of patients cannot be excluded [21] . The levels of the soluble isoforms of VCAM-1 and ICAM-1 are increased in the CSF of patients with stroke, subarachnoid hemorrhage, or traumatic head injuries [12] . There is no difference in the serum levels of these adhesion molecules between the MMD and control groups [21] .
A possible interaction between the immune system and the vessel wall has been suggested in MMD. Inflammatory stimuli can induce cytokines, which include interleukin-1 (IL-1) and TGF- b [11] . IL-1 induces release of TGF- b 1 from SMCs and from inflammatory cells in MMD
67 Proteins, Cells, and Immunity in the Moyamoya Disease
patients. TGF- b 1 may modulate the expression of the elastin gene and elastin accumulation in arterial SMCs in MMD patients [11] . The stimulation of cells with interleukin-1 b (IL-1 b ) led to a significantly greater release of prostaglandin E 2 (PGE 2 ) into the medium (compared with control SMCs) via the activation of cyclooxygenase-2 (COX-2) from MMD SMCs [22] . Excessive amounts of PGE 2 may increase vascular permeability and decrease vascular tone, thus facilitating exposure of the vessels to blood constituents, including growth factors and cytokines that might induce and promote the development of intimal thickening in MMD [22] . Excessive amounts of PGE 2 also inhibit the migration and proliferation of SMCs that might be necessary for the rapid repair of vascular wall injury, which results in the continued increase in vascular permeability and facilitates the prolonged exposure of vessels to blood constituents [22] . The stimulation of SMCs with IL-1 led to the expression of inducible nitric oxide (NO) synthetase and the release of NO [22] . NO is an endothelium-derived relaxing factor that regulates vascular tone and inhibits SMC migration [23] .
Autoimmunity may also be relevant to MMD, as autoantibodies are more frequently detected in the serum and CSF of these patients than in those of control subjects [1, 24] . The histological findings in the vessels are also considered similar to the chronic inflammatory changes observed in polyarteritis or in Kawasaki’s disease [1] . However, the paucity of other inflammatory features, both histological and biochemical, opposes this view [1] . Even though an autoimmune process has been implicated in MMD, further studies are required to elucidate the direct participation of autoimmunity in the pathological changes of this disease.
Thrombogenesis has been implicated in MMD as a causative factor [1] . Systematic analyses seeking evidence of a thrombotic tendency in MMD have revealed that one-third of the patients examined had either congenital or acquired tendencies that favored throm- bosis [25] . Prothrombotic states or thrombophilia sometimes accompany angiographic find- ings similar to MMD and result in cerebral infarction. These findings suggest that thrombi may play either an essential role or a contributory role in MMD and in the consequent cerebral ischemia.
In spite of enthusiastic research efforts, the pathogenesis of MMD remains enigmatic. It is not clear whether these factors are causative or are simply associated with disease pathogenesis;
for example, they may contribute to the angiogenesis associated with this disease or may be an epiphenomenon that results from recurrent strokes. Further studies are required to determine whether these factors represent potential diagnostic or therapeutic targets for the management of MMD.
References
1. Ikezaki K, Kono S, Fukui M (2001) Etiology of moyamoya disease: pathology, pathophysiology, and genetics. In: Ikezaki K, Loftus CM (eds) Moyamoya disease. Rolling Meadows: American Association of Neurological Surgeons
2. Kono S, Oka K, Sueishi K (1990) Histopathologic and morphometric studies of leptomeningeal vessels in moyamoya disease. Stroke 21:1044–1050
3. Hoshimaru M, Takahashi JA, Kikuchi H et al (1991) Possible roles of basic fibroblast growth factor in the pathogenesis of moyamoya disease: an immunohistochemical study. J Neurosurg 75:267–270 4. Malek AM, Connors S, Robertson RL et al (1997) Elevation of cerebrospinal fluid levels of basic fibro- blast growth factor in moyamoya and central nervous system disorders. Pediatr Neurosurg 27:182–189 5. Suzui H, Hoshimaru M, Takahashi JA et al (1994) Immunohistochemical reactions for fibroblast
growth factor receptor in arteries of patients with moyamoya disease. Neurosurgery 35:20–25
68 S.-K. Kim et al.
6. Takahashi A, Sawamura Y, Houkin K et al (1993) The cerebrospinal fluid in patients with moyamoya disease (spontaneous occlusion of the circle of Willis) contains high level of basic fibroblast growth factor. Neurosci Lett 160:214–216
7. Yoshimoto T, Houkin K, Takahashi A et al (1996) Angiogenic factors in moyamoya disease. Stroke 27:2160–2165
8. Hojo M, Hoshimaru M, Miyamoto S et al (1998) Role of transforming growth factor-beta1 in the pathogenesis of moyamoya disease. J Neurosurg 89:623–629
9. Aoyagi M, Fukai N, Sakamoto H et al (1991) Altered cellular responses to serum mitogens, includ- ing platelet-derived growth factor, in cultured smooth muscle cells derived from arteries of patients with moyamoya disease. J Cell Physiol 147:191–198
10. Kubo H (1993) Angiogenesis on encephalo-myo-synangiosis. The effect of basic fibroblast growth factor. Nippon Geka Hokan 62:82–91 (in Japanese)
11. Yamamoto M, Aoyagi M, Tajima S et al (1997) Increase in elastin gene expression and protein synthesis in arterial smooth muscle cells derived from patients with Moyamoya disease. Stroke 28:
1733–1738
12. Nanba R, Kuroda S, Ishikawa T et al (2004) Increased expression of hepatocyte growth factor in cerebrospinal fluid and intracranial artery in moyamoya disease. Stroke 35:2837–2842
13. Kim SK, Yoo JI, Cho BK et al (2003) Elevation of CRABP-I in the cerebrospinal fluid of patients with Moyamoya disease. Stroke 34:2835–2841
14. Takagi Y, Kikuta K, Nozaki K et al (2007) Expression of hypoxia-inducing factor-1 alpha and endoglin in intimal hyperplasia of the middle cerebral artery of patients with Moyamoya disease. Neurosurgery 60:338–345
15. Yoshihara T, Taguchi A, Matsuyama T et al (2008) Increase in circulating CD34-positive cells in patients with angiographic evidence of moyamoya-like vessels. J Cereb Blood Flow Metab 28:1086–1089 16. Folkman J, Shing Y (1992) Angiogenesis. J Biol Chem 267:10931–10934
17. Isner JM, Asahara T (1999) Angiogenesis and vasculogenesis as therapeutic strategies for postnatal neovascularization. J Clin Invest 103:1231–1236
18. Jung KH, Chu K, Lee ST et al (2008) Circulating endothelial progenitor cells as a pathogenetic marker of moyamoya disease. J Cereb Blood Flow Metab 28:1795–1803
19. Rafat N, Beck GCh, Peña-Tapia PG et al (2009) Increased levels of circulating endothelial progenitor cells in patients with Moyamoya disease. Stroke 40:432–438
20. Masuda J, Ogata J, Yutani C (1993) Smooth muscle cell proliferation and localization of macrophages and T cells in the occlusive intracranial major arteries in moyamoya disease. Stroke 24:1960–1967 21. Soriano SG, Cowan DB, Proctor MR et al (2002) Levels of soluble adhesion molecules are elevated
in the cerebrospinal fluid of children with moyamoya syndrome. Neurosurgery 50:544–549 22. Yamamoto M, Aoyagi M, Fukai N et al (1999) Increase in prostaglandin E(2) production by
interleukin-1beta in arterial smooth muscle cells derived from patients with moyamoya disease.
Circ Res 85:912–918
23. Noda A, Suzuki Y, Takayasu M et al (2000) Elevation of nitric oxide metabolites in the cerebrospinal fluid of patients with moyamoya disease. Acta Neurochir (Wien) 142:1275–1280
24. Kim J, Kim SK, Wang KC et al (2004) SEREX identification of the autoantibodies that are prevalent in the cerebrospinal fluid of patients with moyamoya disease. Biotechnol Lett 26:585–588 25. Tsuda H, Hattori S, Tanabe S et al (1997) Thrombophilia found in patients with moyamoya disease.
Clin Neurol Neurosurg 99 (Suppl 2):S229–233
69 The characteristic findings of intimal thickening and resulting steno-occlusion at the termi- nal portion of the internal carotid artery (ICA) along with pathological changes in neigh- boring arteries have been enumerated in the guidelines for the diagnosis of moyamoya disease [1, 2] . Fibrocellular thickening of the intima, an irregular disruption of the internal elastic lamina, and the attenuation of the media are the main findings [1, 3] . These findings have been observed not only in the carotid fork but also in cortical branches of the middle cerebral artery (MCA) [1, 3, 4] . In perforating arteries, microaneurysm formation and fragmented elastic lamina have been detected, and these are considered to be one of the reasons for intracerebral hemorrhage [1] . Sometimes, extracranial arteries such as superior temporal arteries (STA) and renal arteries have also been shown to be affected by the same stenotic changes, so that moyamoya disease can be considered to be a kind of systemic diseases [5] .
Increased level of several growth factors and their receptors including basic fibroblast growth factor (bFGF), transforming growth factor-beta (TGF-beta), and hepatocyte growth factor (HGF) have been detected in the STA and ICA [5– 8] . Using immunohistochemical methods, these factors were elevated in vascular walls [5– 8] . In previous studies, expressions of growth factors and cytokines in cerebrospinal fluid (CSF) have been analyzed. According to these reports, bFGF, TGF-beta, and HGF were also elevated in CSF [5– 8] . These observa- tions indicate that elevated growth factors may affect the surrounding tissue and cells. Growth factors may affect the growth and characteristic change of vascular smooth muscle cells and induce thickening of intima. In addition, it is possible that they influence the formation of transdural anastomosis which is a special characteristic of moya moya disease.
Besides the growth factors, several cytokines were supposed to be involved in moyamoya disease. Overproduction of prostaglandin E(2) and nitric oxide metabolite was reported by different analyzes in previous studies [9, 10] . Concentrations of soluble vascular-cell adhesion molecule type 1, intracellular adhesion molecule type 1, and E-selection in the CSF are also increased in moyamoya disease [6] . These factors are related to the inflammatory process and known to be induced in activated endothelial cells. During atherogenesis, they are induced in endothelial cells. Thus, they may be closely related with intimal hyperplasia in moyamoya Y. Takagi (!)
Department of Neurosurgery , Kyoto University Graduate School of Medicine , 54 Kawahara-cho, Sakyo , Kyoto , 606-8507 , Japan
e-mail: [email protected]