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]
Vascular Smooth Muscle Cell-Related Molecules
70 Y. Takagi
Fig. 2 Immunohistochemical analysis for single-stranded DNA (ssDNA). Immunopositive cells from ssDNA were detected in the specimens from a patient with moyamoya disease ( a , b ) but not in those from the control patient ( c ). Immunohistochemical analysis for cleaved caspase-3. Immunopositive cells for cleaved caspase-3 were detected in the specimens from moyamoya disease ( d , e ) but not in those from the control patient ( f ). Original magnification, ×100
Fig. 1 Photographs of specimens of the middle cerebral artery taken from patients with or without moyamoya disease (hematoxylin and eosin stain). The sample from a patient with moyamoya disease shows intimal hyperplasia ( a ) and that from the control patient does not ( b ). Original magnification ×100
71 Growth Factors, Cytokines and Adhesion Molecules
disease. Concerning the molecules related to the extracellular matrix which plays a role in cerebral hemorrhage and angiogenesis, matrix metalloproteinase-9 (MMP-9) has been analyzed. Serum level of MMP-9 was elevated in moyamoya disease [7] .
Several studies using cultured smooth muscle cells from the patients with moyamoya dis- ease have been reported [2, 10– 12] . Among them, the involvement of platelet-derived growth factor (PDGF), prostaglandin E(2), and elastin in moyamoya disease were clarified [8, 9, 13] . Prostaglandin E(2) production stimulated by interleukin-1 beta was elevated in smooth mus- cle cells from patients with moyamoya disease [8] . Responses to PDGF and IL-1 beta in migration and DNA synthesis were different between smooth muscle cells from those with moyamoya disease and from control patients [8, 14] . In addition, smooth muscle cells derived from patients with moyamoya disease show increased elastin synthesis stimulated by TGF- beta [9] . These observations indicates that intracellular signal transduction in the cells of moyamoya disease differs from that in normal cells. The different expressions growth fac- tors, other molecules and intracellular signal transduction have the possibility to affect the extent of angiogenesis and intimal hyperplasia of intracranial and extracranial arteries.
Recently, surgical specimens obtained at bypass surgery were used in histopathological studies [15– 17] . In these studies, the specimens from the distal part of the MCA were analyzed.
Intimal hyperplasia, disruption of internal elastic lamina, and thinning of media were obvious in the distal part of the MCA as well as in the ICA (Fig. 1 ) [4] . Furthermore, apoptosis related to caspase-3 was detected in intima and media of distal MCA from patients with moyamoya disease (Fig. 2 ) [18] . Concerning intimal hyperplasia, hypoxia-inducing factor 1- a was reported to be induced in hyperplastic intima of moyamoya disease [15] .
In summary, intimal hyperplasia and medial thinness in patients with moyamoya disease are affected by expressions of growth factors, cytokines, and adhesion molecules. In addition, cellular response against stimuli is also changed from the normal condition. This phenomenon is not limited to the terminal portion of internal cerebral artery but also occurs in the periph- eral portion of the MCA.
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