Cerebral cavernous malformations (CCMs) are vascular lesions predominantly developing in the central nervous system (CNS), with no effective treatments other than surgery. Loss-of-function mutation in CCM1/krev interaction trapped 1 (KRIT1), CCM2, or CCM3/programmed cell death 10 (PDCD10) causes lesions that are characterized by abnormal vascular integrity. Vascular endothelial cadherin (VE-cadherin), a major regulator of endothelial cell (EC) junctional integrity is strongly disorganized in ECs lining the CCM lesions. We report here that microRNA-27a (miR-27a), a negative regulator of VE-cadherin, is elevated in ECs isolated from mouse brains developing early CCM lesions and in cultured ECs with CCM1 or CCM2 depletion. Furthermore, we show miR-27a acts downstream of kruppel-like factor (KLF)2 and KLF4, two known key transcription factors involved in CCM lesion development. Using CD5-2 (a target site blocker [TSB]) to prevent the miR-27a/VE-cadherin mRNA interaction, we present a potential therapy to increase VE-cadherin expression and thus rescue the abnormal vascular integrity. In CCM1- or CCM2-depleted ECs, CD5-2 reduces monolayer permeability, and in Ccm1 heterozygous mice, it restores dermal vessel barrier function. In a neonatal mouse model of CCM disease, CD5-2 normalizes vasculature and reduces vascular leakage in the lesions, inhibits the development of large lesions, and significantly reduces the size of established lesions in the hindbrain. Furthermore, CD5-2 limits the accumulation of inflammatory cells in the lesion area. Our work has established that VE-cadherin is a potential therapeutic target for normalization of the vasculature and highlights that targeting miR-27a/VE-cadherin interaction by CD5-2 is a potential novel therapy for the devastating disease, CCM.

脑海绵状畸形（CCM）是主要在中枢神经系统（CNS）中发展的血管病变，除手术外没有其他有效的治疗方法。捕获的CCM1 / krev相互作用1（KRIT1），CCM2或CCM3 /程序性细胞死亡10（PDCD10）的功能丧失突变导致以血管完整性异常为特征的病变。血管内皮钙黏着蛋白（VE-cadherin）是内皮细胞（EC）连接完整性的主要调节剂，在CCM内衬的EC中强烈地杂乱无章。我们在这里报告说，microRNA-27a（miR-27a），VE-钙黏着蛋白的负调节剂，在从小鼠脑中发展为早期CCM病变的分离的EC和培养的CCM1或CCM2耗竭的EC中升高。此外，我们显示miR-27a在kruppel样因子（KLF）2和KLF4的下游起作用，CCM病变发展涉及两个已知的关键转录因子。我们使用CD5-2（靶位阻滞剂[TSB]）来防止miR-27a / VE-钙黏着蛋白mRNA相互作用，我们提出了一种潜在的疗法来增加VE-钙黏着蛋白的表达，从而挽救异常的血管完整性。在CCM1或CCM2耗尽的EC中，CD5-2降低单层渗透性，而在Ccm1杂合小鼠，它恢复真皮血管屏障功能。在CCM疾病的新生小鼠模型中，CD5-2使脉管系统正常化并减少病变中的血管渗漏，抑制大病变的发展，并显着减小后脑中已建立病变的大小。此外，CD5-2限制了炎性细胞在病变区域的积累。我们的工作已确定，VE-钙粘着蛋白是使脉管系统正常化的潜在治疗靶标，并强调通过CD5-2靶向miR-27a / VE-钙粘着蛋白相互作用是毁灭性疾病CCM的潜在新疗法。