PDF(Pubmed)
Abstract：
Upregulation of Notch signaling is associated with brain arteriovenous malformation (bAVM), a disease that lacks pharmacological treatments. Tetracycline (tet)-regulatable endothelial expression of constitutively active Notch4 (Notch4*tetEC) from birth induced bAVMs in 100% of mice by P16. To test whether targeting downstream signaling, while sustaining the causal Notch4*tetEC expression, induces AVM normalization, we deleted Rbpj, a mediator of Notch signaling, in endothelium from P16, by combining tet-repressible Notch4*tetEC with tamoxifen-inducible Rbpj deletion. Established pathologies, including AV connection diameter, AV shunting, vessel tortuosity, intracerebral hemorrhage, tissue hypoxia, life expectancy, and arterial marker expression were improved, compared with Notch4*tetEC mice without Rbpj deletion. Similarly, Rbpj deletion from P21 induced advanced bAVM regression. After complete AVM normalization induced by repression of Notch4*tetEC, virtually no bAVM relapsed, despite Notch4*tetEC re-expression in adults. Thus, inhibition of endothelial Rbpj halted Notch4*tetEC bAVM progression, normalized bAVM abnormalities, and restored microcirculation, providing proof of concept for targeting a downstream mediator to treat AVM pathologies despite a sustained causal molecular lesion.
摘要：
Notch信号上调与脑动静脉畸形（bAVM）有关，缺乏药物治疗的疾病。通过P16在100%小鼠中来自出生诱导的bAVM的组成型活性Notch4(Notch4*tetEC)的四环素(tet)-可调节的内皮表达。要测试是否针对下游信令，在维持因果Notch4*tetEC表达的同时，诱导AVM正常化，我们删除了Rbpj,Notch信号的调停者,在P16的内皮中，通过将tet抑制的Notch4*tetEC与他莫昔芬诱导的Rbpj缺失相结合。既定的病理学，包括AV连接直径，AV分流,血管弯曲，脑出血，组织缺氧，预期寿命,动脉标志物表达得到改善，与无Rbpj缺失的Notch4*tetEC小鼠相比。同样，来自P21的Rbpj缺失诱导了晚期bAVM回归。在抑制Notch4*tetEC诱导的完全AVM正常化后，几乎没有bAVM复发，尽管Notch4*tetEC在成人中重新表达。因此，抑制内皮Rbpj阻止Notch4*tetECbAVM进展，标准化的bAVM异常，恢复了微循环，尽管存在持续的因果分子损伤，但仍提供靶向下游介质治疗AVM病理的概念证明。
