KRIT1 mutations are the most common cause of cerebral cavernous malformation (CCM). Acute Krit1 gene inactivation in mouse brain microvascular endothelial cells (BMECs) changes expression of multiple genes involved in vascular development. These changes include suppression of Thbs1, which encodes thrombospondin1 (TSP1) and has been ascribed to KLF2- and KLF4-mediated repression of Thbs1. In vitro reconstitution of TSP1 with either full-length TSP1 or 3TSR, an anti-angiogenic TSP1 fragment, suppresses heightened vascular endothelial growth factor signaling and preserves BMEC tight junctions. Furthermore, administration of 3TSR prevents the development of lesions in a mouse model of CCM1 (Krit1^ECKO) as judged by histology and quantitative micro-computed tomography. Conversely, reduced TSP1 expression contributes to the pathogenesis of CCM, because inactivation of one or two copies of Thbs1 exacerbated CCM formation. Thus, loss of Krit1 function disables an angiogenic checkpoint to enable CCM formation. These results suggest that 3TSR, or other angiogenesis inhibitors, can be repurposed for TSP1 replacement therapy for CCMs.

KRIT1突变是脑海绵状畸形（CCM）的最常见原因。小鼠脑微血管内皮细胞（BMEC）中的急性Krit1基因失活改变了参与血管发育的多个基因的表达。这些变化包括Thbs1的抑制，该Thbs1编码血小板反应蛋白1（TSP1），并已归因于KLF2和KLF4介导的Thbs1抑制。用全长TSP1或3TSR（一种抗血管生成TSP1片段）体外重建TSP1，可抑制血管内皮生长因子信号转导升高并保留BMEC紧密连接。此外，3TSR的施用防止在CCM1的小鼠模型病变的发展（Krit1 ^ECKO），由组织学和定量显微计算机断层扫描判断。相反，减少的TSP1表达有助于CCM的发病机理，因为Thbs1的一个或两个拷贝的失活加剧了CCM的形成。因此，Krit1功能的丧失会禁用血管生成检查点以启用CCM形成。这些结果表明，3TSR或其他血管生成抑制剂可用于CCM的TSP1替代治疗。