Pericytes as a new target for pathological processes in CADASIL
Pericytes as a new target for pathological processes in CADASIL
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DOI：
10.1111/j.1440-1789.2011.01290.x
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发表时间：
2012-10-01
期刊：
影响因子：
2.3
通讯作者：
Lewandowska, Eliza
中科院分区：
文献类型：
--
作者：
Dziewulska, Dorota;Lewandowska, Eliza
CADASIL是由NOTCH 3基因突变引起的全身性血管病，导致小动脉和小动脉中的血管平滑肌细胞（VSMC）变性和丢失。由于NOTCH 3基因编码的受体蛋白不仅在VSMC上表达，而且在周细胞上也表达，因此CADASIL可损伤周细胞和毛细血管。为了验证这一假设，我们检查了CADASIL患者尸检大脑和皮肤肌肉活检中的微血管。我们发现毛细血管周细胞变性和丢失。周细胞皱缩，胞质内有大量空泡、大泡状结构和增大的病理性线粒体复合体。在内皮细胞周细胞连接内也观察到退行性变化，特别是在钉窝连接内。在周细胞膜附近或内折处，常可见颗粒状嗜锇物质（GOM）沉积。在受影响的毛细血管中，内皮细胞表现出变性、选择性死亡或肿胀的特征，导致毛细血管腔变窄或闭塞。我们的研究结果表明，在CADASIL不仅VSMC，而且周细胞严重受损。CADASIL中的周细胞参与可导致毛细血管通透性增加和脑微循环障碍，从而导致白色物质损伤。由于在毛细血管中，周细胞调节血管收缩性，它们的变性也可能导致血管反应性缺陷，这是在血管壁发生组织病理学变化之前，在CADASIL中很早就观察到的现象。
CADASIL is a generalized angiopathy caused by mutations in NOTCH 3 gene leading to degeneration and loss of vascular smooth muscle cells (VSMC) in small arteries and arterioles. Since the receptor protein encoded by NOTCH 3 gene is expressed not only on VSMC but also on pericytes, pericytes and capillary vessels can be damaged by CADASIL. To check this hypothesis we examined microvessels in autopsy brains and skin-muscle biopsies of CADASIL patients. We found degeneration and loss of pericytes in capillary vessels. Pericytes were shrunken and their cytoplasm contained numerous vacuoles, big vesicular structures and complexes of enlarged pathological mitochondria. Degenerative changes were also observed within endothelial-pericytic connections, especially within peg-and-socket junctions. Nearby pericyte cell membranes or inside infoldings, deposits of granular osmiophilic material (GOM) were usually seen. In the affected capillaries endothelial cells revealed features of degeneration, selective death or swelling, leading to narrowing or occlusion of the capillary lumen. Our findings indicate that in CADASIL not only VSMC but also pericytes are severely damaged. Pericyte involvement in CADASIL can result in increased permeability of capillary vessels and disturbances in cerebral microcirculation, leading to white matter injury. Since in capillaries pericytes regulate vessel contractility, their degeneration can also cause defective vasomotor reactivity, the phenomenon observed very early in CADASIL, before development of histopathological changes in vessel walls.