Blocking Signalopathic Events to Treat Cerebral Cavernous Malformations

Cerebral cavernous malformations (CCMs) are pathologies of the brain vasculature characterized by capillary-venous angiomas that result in recurrent cerebral hemorrhages. Familial forms are caused by a clonal loss of any of three CCM genes in endothelial cells, which causes the activation of a novel pathophysiological pathway involving mitogen-activated protein kinase and Kruppel-like transcription factor KLF2/4 signaling. Recent work has shown that cavernomas can undergo strong growth when CCM-deficient endothelial cells recruit wild-type neighbors through the secretion of cytokines. This suggests a treatment strategy based on targeting signalopathic events between CCM-deficient endothelial cells and their environment. Such approaches will have to consider recent evidence implicating ‘third hits’ from hypoxia-induced angiogenesis signaling or the microbiome in modulating the development of cerebral hemorrhages.