Vascular permeability in cerebral cavernous malformations
Vascular permeability in cerebral cavernous malformations
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DOI：
10.1038/jcbfm.2015.98
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发表时间：
2015-10-01
影响因子：
6.3
通讯作者：
Awad, Issam A.
中科院分区：
文献类型：
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作者：
Mikati, Abdul G.;Khanna, Omaditya;Awad, Issam A.
家族性脑海绵状血管畸形（CCM）患者的CCM1、CCM2或CCM3基因单倍不足。相应CCM蛋白的丢失增加RhoA激酶介导的体外内皮通透性，并在小鼠脑中在体内。一项前瞻性病例对照观察性研究通过动态对比增强定量灌注磁共振成像，与无家族性疾病的CCM病例相比，研究了家族性CCM受试者的大脑是否显示血管通透性过高，以及病变或脑血管通透性是否与CCM疾病活动相关。在远离病变的白色物质（WMF）的渗透性在家族性病例中显著高于散发性病例，但在CCM病变中相似。在散发性患者中，WMF的渗透性随着年龄的增长而增加，但在家族性病例中则不然。与具有较轻疾病表型但病变渗透性相似的患者相比，具有更侵袭性的家族性CCM疾病患者具有更大的WMF渗透性。接受他汀类药物治疗常规心血管适应症的受试者具有较低WMF（但非病变）渗透性的趋势。这是第一次证明脑血管通透性过高的人与常染色体显性遗传疾病，作为预测机制。脑渗透性，而不是病变的渗透性，可以作为CCM疾病活动的生物标志物，并帮助校准潜在的药物治疗。
Patients with the familial form of cerebral cavernous malformations (CCMs) are haploinsufficient for the CCM1, CCM2, or CCM3 gene. Loss of corresponding CCM proteins increases RhoA kinase-mediated endothelial permeability in vitro, and in mouse brains in vivo. A prospective case-controlled observational study investigated whether the brains of human subjects with familial CCM show vascular hyperpermeability by dynamic contrast-enhanced quantitative perfusion magnetic resonance imaging, in comparison with CCM cases without familial disease, and whether lesional or brain vascular permeability correlates with CCM disease activity. Permeability in white matter far (WMF) from lesions was significantly greater in familial than in sporadic cases, but was similar in CCM lesions. Permeability in WMF increased with age in sporadic patients, but not in familial cases. Patients with more aggressive familial CCM disease had greater WMF permeability compared to those with milder disease phenotype, but similar lesion permeability. Subjects receiving statin medications for routine cardiovascular indications had a trend of lower WMF, but not lesion, permeability. This is the first demonstration of brain vascular hyperpermeability in humans with an autosomal dominant disease, as predicted mechanistically. Brain permeability, more than lesion permeability, may serve as a biomarker of CCM disease activity, and help calibrate potential drug therapy.