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Role of Delta-Notch signaling in cerebral cavernous malformations

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Abstract

Cerebral cavernous malformations (CCM) commonly known as cavernous hemangioma are associated with abnormally enlarged thin-walled blood vessels. As a result, these dilated capillaries are prone to leakage and result in hemorrhages. Clinically, such hemorrhages lead to severe headaches, focal neurological deficits, and epileptic seizures. CCM is caused by loss of function mutations in one of the three well-known CCM genes: Krev interaction trapped 1 (KRIT1), OSM, and programmed cell death 10 (PDCD10). Loss of CCM genes have been shown to be synergistically related to decreased Notch signaling and excessive angiogenesis. Despite recent evidences indicating that Notch signaling plays a pivotal role in regulating angiogenesis, the role of Notch in CCM development and progression is still not clear. Here, we provide an update literature review on the current knowledge of the structure of Notch receptor and its ligands, its relevance to angiogenesis and more precisely to CCM pathogenesis. In addition to reviewing the current literatures, this review will also focus on the cross talk between Delta-Notch and vascular endothelial growth factor (VEGF) signaling in angiogenesis and in CCM pathogenesis. Understanding the role of Notch signaling in CCM development and progression might help provide a better insight for novel anti-angiogenic therapies.

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Andreas Fischer, Heidelberg, Germany

Cerebral cavernous malformations (CCM) are slow-flow neurovascular lesions, which put patients at risk for developing intracranial hemorrhages, focal neurological deficits, and epileptic seizures. In the vast majority of familial CCM cases autosomal-dominantly inherited heterozygous inactivating mutations in three genes, CCM1 (KRIT1), CCM2 (MGC4607), and CCM3 (PDCD10) can be found. It was assumed that a “second hit” in brain endothelial cells may lead to inactivation of the second allele. This biallelic loss of a CCM gene would then initiate lesion development (REFERENCE PMID: 19088123; PMID: 19088124). Therapeutic options for patients suffering from multiple lesions are very limited. Therefore, a better understanding of the CCM pathogenesis is essential to develop pharmaceutical interventions. However, we are still very far away from this ultimate goal. One needs to better understand the functions of the three CCM genes and in particular the signaling events downstream of CCM proteins (Rho kinase, MAPK, integrin activation, AKT, VEGF, Notch) to identify “druggable” targets.

In line with this notion, the review presented here by Dr. Kar and colleagues sheds light on the current knowledge of Notch and VEGF signaling downstream of CCM1–3 proteins. In several experimental settings using cultured endothelial cells or mice in which CCM1 or CCM3 was deleted specifically in endothelial cells, decreased activity of Notch signaling was observed (references are listed in the review article by Dr. Kar). Although the link from CCM proteins to Notch signaling activation is still a mystery, this observation may help to better understand the biology of CCMs. In the developing vasculature, Notch signaling gets dynamically upregulated and downregulated, and this alters the expression of VEGF receptors and the competence of endothelial cells to form a novel vessel sprout (REFERENCE PMID: 20871601). As such, impaired Notch signaling activity upon loss of CCM genes would strongly contribute to excessive vessel formation and impaired coverage of endothelial tubes with mural cells in CCMs.

However, several open questions remain. (1) It is still very difficult to determine the activation status of Notch signaling in human patient samples. Use of latest RNA sequencing techniques on the single cell level may help to resolve this in the near future. (2) It is still unknown how CCM proteins control Notch signaling. (3) The role of Notch signaling in the quiescent adult endothelium is very poorly understood. Interestingly, pharmacological blockade of Notch signaling with monoclonal DLL4 antibodies led to formation of benign vascular tumors (REFERENCE PMID: 20147986). This suggests that Notch signaling is needed to actively maintain a quiescent endothelium. (4) One needs to figure out how CCM genes are needed to keep endothelial cells in the adult brain in a resting state. There are inducible knockout mouse models for CCM1–3 available, which develop CCM-like lesion (REFERENCE PMID: 21859843; PMID: 23748444). Thus far, gene ablation was induced in the perinatal period in which the vasculature is still very active. Local inactivation of CCM genes in the adult brain will be better suited to mimic the human situation. Such an approach, together with careful monitoring of Notch activity in blood vessels, will be of utmost importance to definitely judge about the role of Notch signaling in CCM pathogenesis.

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Kar, S., Baisantry, A., Nabavi, A. et al. Role of Delta-Notch signaling in cerebral cavernous malformations. Neurosurg Rev 39, 581–589 (2016). https://doi.org/10.1007/s10143-015-0699-y

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