Calm the raging hormone - a new therapeutic strategy involving progesterone-signaling for hemorrhagic CCMs

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 worse symptoms frequently occurring after surgery. Therefore, there is a grave need for the identification of molecular targets for therapeutic treatment and biomarkers as risk predictors for hemorrhagic stroke prevention. Based on the various perturbed angiogenic signaling cascades mediated by the CCM signaling complex (CSC) reported, 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 CSC stability to prevent the devastating outcome of hemorrhagic CCMs.