Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Cold Spring Harb Perspect Med. 2023 Mar 1;13(3):a041188. doi: 10.1101/cshperspect.a041188.
Cerebral cavernous malformations (CCMs), consisting of multiple, dilated capillary channels formed by a single layer of endothelium and lacking parenchymal cells, are exclusively to the brain. Patients with inherited autosomal-dominant CCMs carry loss-of-function mutations in one of three genes: CCM1, CCM2, and CCM3. It is not known why CCM lesions are confined to brain vasculature despite the ubiquitous expression of CCM proteins in all tissues, and whether cell types other than endothelial cells (ECs) contribute to CCM lesion formation. The prevailing view is that the primary defects in CCMs in humans are EC-intrinsic, such that EC-specific deletion of any one of the three genes in mice results in similar CCM lesions. An unexpected finding is that Ccm3 deletion in pericytes (PCs) also induces CCM lesions. CCM3 deletion in ECs or PCs destabilizes PC-EC associations, highlighting the importance of these interactions in CCM formation.
脑内海绵状血管畸形（CCMs）由单层内皮细胞形成的多个扩张的毛细血管通道组成，不存在实质细胞，仅发生于脑内。携带常染色体显性遗传 CCM 突变的患者在三个基因中的一个发生功能丧失性突变：CCM1、CCM2 和 CCM3。尽管 CCM 蛋白在所有组织中普遍表达，但 CCM 病变为何局限于脑血管，以及除内皮细胞（ECs）以外的细胞类型是否有助于 CCM 病变形成，目前尚不清楚。目前的观点认为，人类 CCM 的主要缺陷是 EC 内在的，因此在小鼠中特异性敲除三个基因中的任何一个，都会导致类似的 CCM 病变。一个意外的发现是，周细胞（PCs）中 Ccm3 的缺失也会诱导 CCM 病变。ECs 或 PCs 中 CCM3 的缺失破坏了 PC-EC 的关联，突出了这些相互作用在 CCM 形成中的重要性。
