Calm the raging hormone - A new therapeutic strategy involving progesterone-signaling for hemorrhagic CCMs.
Calm the raging hormone - A new therapeutic strategy involving progesterone-signaling for hemorrhagic CCMs.
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DOI：
10.20517/2574-1209.2021.64
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发表时间：
2021-07
期刊：
影响因子：
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通讯作者：
Jun Zhang;Johnathan Abou-Fadel
中科院分区：
文献类型：
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作者：
Jun Zhang;Johnathan Abou-Fadel
脑海绵状血管畸形（CCM）是最常见的血管畸形之一，其特征是颅内微血管毛细血管异常扩张，导致出血性卒中的易感性增加。作为一种不完全显性遗传的常染色体显性遗传病，大多数CCM基因突变携带者在很大程度上是无症状的，但当症状发生时，疾病通常已达到局灶性出血伴不可逆脑损伤的阶段，而启动CCM病理发生的分子"触发"仍然难以捉摸。目前，尽管手术后经常出现更严重的症状复发，但侵入性神经外科手术切除CCM病变是治疗的唯一选择。因此，迫切需要鉴定用于治疗性治疗的分子靶标和作为出血性卒中预防的风险预测因子的生物标志物。基于报道的由CCM信号复合物（CSC）介导的各种扰动的血管生成信号级联，已经提出了许多候选药物，靶向由于CCM蛋白之一的功能丧失而失调的潜在血管生成相关信号通路，这可能不足以纠正病理表型，出血性CCM。在这篇综述中，我们描述了一个新的范式出血性CCM病变的机制，并提出了一个新的概念，确保CSC的稳定性，以防止破坏性的结果出血性CCM。
Cerebral cavernous malformations (CCMs), one of the most common vascular malformations, are characterized by abnormally dilated intracranial microvascular capillaries resulting in increased susceptibility to hemorrhagic stroke. As an autosomal dominant disorder with incomplete penetrance, the majority of CCMs gene mutation carriers are largely asymptomatic but when symptoms occur, the disease has typically reached the stage of focal hemorrhage with irreversible brain damage, while the molecular "trigger" initiating the occurrence of CCM pathology remain elusive. Currently, the invasive neurosurgery removal of CCM lesions is the only option for the treatment, despite the recurrence of the worse symptoms frequently occurring after surgery. Therefore, there is a grave need for identification of molecular targets for therapeutic treatment and biomarkers as risk predictors for hemorrhagic stroke prevention. Based on reported various perturbed angiogenic signaling cascades mediated by the CCM signaling complex (CSC), there have been many proposed candidate drugs, targeting potentially angiogenic-relevant signaling pathways dysregulated by loss of function of one of the CCM proteins, which might not be enough to correct the pathological phenotype, hemorrhagic CCMs. In this review, we describe a new paradigm for the mechanism of hemorrhagic CCM lesions, and propose a new concept for the assurance of the CSC-stability to prevent the devastating outcome of hemorrhagic CCMs.