No abstract

Cerebral cavernous malformations (CCM) are vascular lesions associated with loss-of-function mutations in one of the three genes encoding KRIT1 (CCM1), CCM2, and PDCD10. Recent understanding of the molecular mechanisms that lead to CCM development is limited. The role of microRNAs (miRNAs) has been demonstrated in vascular pathologies resulting in loss of tight junction proteins, increased vascular permeability and endothelial cell dysfunction. Since the relevance of miRNAs in CCM pathophysiology has not been elucidated, the primary aim of the study was to identify the miRNA-mRNA expression network associated with CCM. Using small RNA sequencing, we identified a total of 764 matured miRNAs expressed in CCM patients compared to the healthy brains. The expression of the selected miRNAs was validated by qRT-PCR, and the results were found to be consistent with the sequencing data. Upon application of additional statistical stringency, five miRNAs (let-7b-5p, miR-361-5p, miR-370-3p, miR-181a-2-3p, and miR-95-3p) were prioritized to be top CCM-relevant miRNAs. Further in silico analyses revealed that the prioritized miRNAs have a direct functional relation with mRNAs, such as MIB1, HIF1A, PDCD10, TJP1, OCLN, HES1, MAPK1, VEGFA, EGFL7, NF1, and ENG, which are previously characterized as key regulators of CCM pathology. To date, this is the first study to investigate the role of miRNAs in CCM pathology. By employing cutting edge molecular and in silico analyses on clinical samples, the current study reports global miRNA expression changes in CCM patients and provides a rich source of data set to understand detailed molecular machinery involved in CCM pathophysiology.

BACKGROUND Due to the complex segmental organization of the brainstem, it is preferable to study midbrain cavernous malformations (MCMs) separately from pontine and medullary lesions. OBJECTIVE To evaluate clinical results after microsurgical removal of MCMs, assess predictors for outcome and introduce a topographical classification of MCMs. METHODS A retrospective study was conducted on consecutive patients who underwent MCM resection. Clinical parameters before and after surgery, morphological CM features, surgical approaches and outcomes were analyzed. MCMs were classified according to their exact location within the midbrain and their axial and sagittal extension. RESULTS The authors reviewed 72 patients (35 male). Lesions varied in size between 4 and 55 mm. The vast majority of patients benefited from surgery. The mean modified Rankin Scale (mRS) decreased significantly from 1.6 at admission to 1.3 at discharge and to 0.7 at follow-up (6-247 mo postoperatively). Five patients (6.9%) suffered from delayed hypertrophic olivary degeneration as visualized on magnetic resonance imaging. One male suffered from early postoperative re-bleeding that required surgical hematoma evacuation. There were no severe long tract impairment or other disabling complications, no delayed re-bleedings, and no surgical mortality. CONCLUSION We present a new topographic classification of MCMs that may be useful for predicting the occurrence of postoperative eye movement disorders. Other predictors of persistent oculomotor disturbances are time interval between onset of symptoms and surgery, and patient's age over 40 yr. Early surgery is recommendable in patients with oculomotor disturbances. MCM size over 18 mm, patient age over 40 yr, and poor mRS at admission are important predictors for the long-term outcome.

Cerebral cavernous malformations (CCM) are common vascular malformation of the brain and are associated with abnormal angiogenesis. Although the exact etiology and the underlying molecular mechanism are still under investigation, recent advances in the identification of the mutations in three genes and their interactions with different signaling pathways have shed light on our understanding of CCM pathogenesis. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is known to play a major role in angiogenesis. Studies have shown that the phosphatase and tensin homologue deleted on chromosome ten (PTEN), a tumor suppressor, is an antagonist regulator of the PI3K/Akt pathway and mediates angiogenesis by activating vascular endothelial growth factor (VEGF) expression. Here, we provide an update literature review on the current knowledge of the PTEN/PI3K/Akt/VEGF signaling in angiogenesis, more importantly in CCM pathogenesis. In addition to reviewing the current literatures, this article will also focus on the structural domain of the three CCM proteins and their interacting partners. Understanding the biology of these proteins with respect to their signaling counterpart will help to guide future research towards new therapeutic targets applicable for CCM treatment.

Cerebral cavernous malformations (CCMs) are low-flow vascular malformations in the brain associated with recurrent hemorrhage and seizures. The current treatment of CCMs relies solely on surgical intervention. Henceforth, alternative non-invasive therapies are urgently needed to help prevent subsequent hemorrhagic episodes. Long non-coding RNAs (lncRNAs) belong to the class of non-coding RNAs and are known to regulate gene transcription and involved in chromatin remodeling via various mechanism. Despite accumulating evidence demonstrating the role of lncRNAs in cerebrovascular disorders, their identification in CCMs pathology remains unknown. The objective of the current study was to identify lncRNAs associated with CCMs pathogenesis using patient cohorts having 10 CCM patients and 4 controls from brain. Executing next generation sequencing, we performed whole transcriptome sequencing (RNA-seq) analysis and identified 1,967 lncRNAs and 4,928 protein coding genes (PCGs) to be differentially expressed in CCMs patients. Among these, we selected top 6 differentially expressed lncRNAs each having significant correlative expression with more than 100 differentially expressed PCGs. The differential expression status of the top lncRNAs, SMIM25 and LBX2-AS1 in CCMs was further confirmed by qRT-PCR analysis. Additionally, gene set enrichment analysis of correlated PCGs revealed critical pathways related to vascular signaling and important biological processes relevant to CCMs pathophysiology. Here, by transcriptome-wide approach we demonstrate that lncRNAs are prevalent in CCMs disease and are likely to play critical roles in regulating important signaling pathways involved in the disease progression. We believe, that detailed future investigations on this set of identified lncRNAs can provide useful insights into the biology and, ultimately, contribute in preventing this debilitating disease.