Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA.
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC.
J Exp Med. 2020 Oct 5;217(10). doi: 10.1084/jem.20200140.
Cerebral cavernous malformations (CCMs) form following loss of the CCM protein complex in brain endothelial cells due to increased endothelial MEKK3 signaling and KLF2/4 transcription factor expression, but the downstream events that drive lesion formation remain undefined. Recent studies have revealed that CCM lesions expand by incorporating neighboring wild-type endothelial cells, indicative of a cell nonautonomous mechanism. Here we find that endothelial loss of ADAMTS5 reduced CCM formation in the neonatal mouse model. Conversely, endothelial gain of ADAMTS5 conferred early lesion genesis in the absence of increased KLF2/4 expression and synergized with KRIT1 loss of function to create large malformations. Lowering versican expression reduced CCM burden, indicating that versican is the relevant ADAMTS5 substrate and that lesion formation requires proteolysis but not loss of this extracellular matrix protein. These findings identify endothelial secretion of ADAMTS5 and cleavage of versican as downstream mechanisms of CCM pathogenesis and provide a basis for the participation of wild-type endothelial cells in lesion formation.
脑内海绵状血管畸形（CCMs）是由于脑内皮细胞中 CCM 蛋白复合物的丢失而形成的，这是由于内皮细胞 MEKK3 信号的增加和 KLF2/4 转录因子表达所致，但驱动病变形成的下游事件仍未定义。最近的研究表明，CCM 病变通过纳入相邻的野生型内皮细胞而扩张，表明存在细胞非自主性机制。在这里，我们发现内皮细胞中 ADAMTS5 的缺失减少了新生小鼠模型中的 CCM 形成。相反，内皮细胞中 ADAMTS5 的获得导致早期病变发生，而不增加 KLF2/4 的表达，并与 KRIT1 功能丧失协同作用，导致大的畸形。降低 versican 的表达减少了 CCM 的负担，表明 versican 是 ADAMTS5 的相关底物，病变的形成需要蛋白水解，但不需要这种细胞外基质蛋白的丢失。这些发现确定了内皮细胞分泌 ADAMTS5 和切割 versican 是 CCM 发病机制的下游机制，并为野生型内皮细胞参与病变形成提供了基础。
