Cerebral cavernous malformations form an anticoagulant vascular domain in humans and mice
Cerebral cavernous malformations form an anticoagulant vascular domain in humans and mice
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DOI：
10.1182/blood-2018-06-856062
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发表时间：
2019-01-17
期刊：
影响因子：
20.3
通讯作者：
Ginsberg, Mark H.
中科院分区：
文献类型：
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作者：
Lopez-Ramirez, Miguel Alejandro;Pham, Angela;Ginsberg, Mark H.
脑海绵状血管瘤（CCM）是常见的脑血管发育不良，容易发生急性和慢性出血并伴有严重的临床后遗症。 CCM 反复出血的发病机制尚不完全清楚。在这里，我们发现 CCM 中的中枢神经系统出血与抗凝内皮受体血栓调节蛋白 (TM) 和内皮蛋白 C 受体 (EPCR) 的局部表达升高有关。人类 CCM 病变以及 CCM 患者血浆中的 TM 水平升高。在小鼠中，Krit1 (Krit1(ECKO)) 或 Pdcd10 (Pdcd10(ECKO)) 的内皮特异性基因失活会导致 CCM 形成，导致血管 TM 和 EPCR 水平增加，以及内皮细胞上活化蛋白 C (APC) 的产生增强。 TM 表达增加是由于 KRIT1 或 PDCD10 缺失导致转录因子 KLF2 和 KLF4 上调。 TM 表达增加会导致 CCM 出血，因为 1 或 2 个 Thbd 基因拷贝的基因失活可减少 Pdcd10(ECKO) 小鼠的脑出血。此外，给予TM和EPCR阻断抗体可显着减少Pdcd10(ECKO)小鼠的CCM出血。因此，产生抗凝 APC 的内皮辅因子的局部增加可能导致 CCM 出血，而血浆可溶性 TM 可能代表 CCM 出血风险的生物标志物。
Cerebral cavernous malformations (CCMs) are common brain vascular dysplasias that are prone to acute and chronic hemorrhage with significant clinical sequelae. The pathogenesis of recurrent bleeding in CCM is incompletely understood. Here, we show that central nervous system hemorrhage in CCMs is associated with locally elevated expression of the anticoagulant endothelial receptors thrombomodulin (TM) and endothelial protein C receptor (EPCR). TM levels are increased in human CCM lesions, as well as in the plasma of patients with CCMs. In mice, endothelial-specific genetic inactivation of Krit1 (Krit1(ECKO)) or Pdcd10 (Pdcd10(ECKO)), which cause CCM formation, results in increased levels of vascular TM and EPCR, as well as in enhanced generation of activated protein C (APC) on endothelial cells. Increased TM expression is due to upregulation of transcription factors KLF2 and KLF4 consequent to the loss of KRIT1 or PDCD10. Increased TM expression contributes to CCM hemorrhage, because genetic inactivation of 1 or 2 copies of the Thbd gene decreases brain hemorrhage in Pdcd10(ECKO) mice. Moreover, administration of blocking antibodies against TM and EPCR significantly reduced CCM hemorrhage in Pdcd10(ECKO) mice. Thus, a local increase in the endothelial cofactors that generate anticoagulant APC can contribute to bleeding in CCMs, and plasma soluble TM may represent a biomarker for hemorrhagic risk in CCMs.