Abstract
Cerebral cavernous malformations (CCMs) are vascular lesions that affect predominantly microvasculature in the brain and spinal cord. CCM can occur either in sporadic or familial form, characterized by autosomal dominant inheritance and development of multiple lesions throughout the patient’s life. Three genes associated with CCM are known: CCM1/KRIT1 (krev interaction trapped 1), CCM2/MGC4607 (encoding a protein named malcavernin), and CCM3/PDCD10 (programmed cell death 10). All the mutations identified in these genes cause a loss of function and compromise the protein functions needed for maintaining the vascular barrier integrity. Loss of function of CCM proteins causes molecular disorganization and dysfunction of endothelial adherens junctions. In this review, we provide an overall vision of the CCM pathology, starting with the genetic bases of the disease, describing the role of the proteins, until we reach the cellular level. Thus, we summarize the genetics of CCM, providing a description of CCM genes and mutation features, provided an updated knowledge of the CCM protein structure and function, and discuss the molecular mechanisms through which CCM proteins may act within endothelial cells, particularly in endothelial barrier maintenance/regulation and in cellular signaling.
Highlights
Cerebral cavernous malformation (CCM) is a disease predominantly affecting neurovasculature
In addition to the role of Rho GTPases in CCM disease, another well-known pathway is represented by the MEKK3 signaling cascade, which is implicated in cell migration and proliferation, and required for proper vessel development [100]
It has been reported that KRIT1/CCM2/PDCD10-mutated endothelial cells are characterized by inadequate autophagy mechanisms, which determine the progression of the disease
Summary
Cerebral cavernous malformation (CCM) is a disease predominantly affecting neurovasculature. These malformations consist of densely packed, enlarged capillary “caverns”. Clustered capillaries are lined by a single layer of endothelium included in a dense collagen matrix, and so characterized by an inhomogeneous vessel wall because of the presence of defective cell–cell junctions This condition results in the impairment of the blood–brain barrier that predisposes it to episodes of thrombosis and bleeding. Clinical signs and symptoms are largely determined by the location, number, and size (from a few millimeters to several centimeters) of the lesions Given that both size and the number of malformations can change over time, new signs and symptoms can arise at every stage of a patient’s life. We focus on gene–protein–disease mechanisms involved in the pathogenesis of CCMs, describing in detail how the identified genes drive the disease, which roles and functions are played by the product of each gene, what networks and signaling pathways are involved in which of these proteins, separately or together [11]
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