In the general population, 1 in 200–250 individuals carries cerebral cavernous malformations (CCM). These individuals may be unaware of this until they begin to suffer from diverse neurological clinical manifestations like seizures or stroke. The vascular malformations, characterized by abnormally enlarged thin-walled vessels lacking smooth muscle support, are prone to hemorrhage. The disease can be either sporadic or inherited. Over the last 10 years, three CCM genes (CCM1–3) have been related to the disease and their discovery has opened the way to an understanding of the disease and pointed to three novel and unsuspected players in angiogenesis.
In this minireview series, we describe recent progress in analyzing new data on the genetics of the disease and the regulation of molecular pathways. We have directed our efforts into surveying what is known about the genetics of the disease, what advances have been made possible by animal models, and the nature of the emerging signaling pathways regulated by CCM proteins.
The first minireview by Riant et al. deals with the genetics of the disease. Almost all the germline mutations encountered in CCM patients are loss-of-function mutations. Because CCM disease is autosomal dominant, what makes lesions occur focally and in multiple sites in the familial cases? Several groups have shown that a ‘two-hit’ mechanism is operating. A somatic mutation, likely acquired in the embryonic or postnatal period, adds to the germline mutation resulting in the complete loss of the two alleles. Interestingly, somatic mutations occur only in endothelial cells and not in the intervening neural tissue. Not all endothelial cells of a lesion carry the somatic mutation. Therefore, it seems that lesions are comprised of a mosaic of wild-type and mutant endothelial cells.
The second minireview by Chan et al. is dedicated to animal models of CCM proteins. Zebrafish and mouse models have been very valuable and complementary in deepening our understanding of the molecular mechanisms underlying CCM pathology. Importantly, zebrafish studies have identified a novel gene named heg and the small GTPase gene rap1b as genetic interactors of Ccm1 and Ccm2 genes. Mutant embryos display major developmental vascular defects leading to death at mid-gestation. Brain seems to be a privileged anatomic site for vascular malformations. Because CCM proteins are more abundantly expressed in neural tissue than in endothelium, an important issue was to determine whether the primary defect lies in neural or endothelial cells. Two groups have obtained proof of an absolute requirement for CCM2 in the endothelium during development, whereas neural expression of CCM2 is not required. Future research will be aimed at generating viable animal models that more faithfully reproduce the human phenotype of CCM during aging. These models would indeed be very valuable for testing pharmacological therapies.
The last minireview by Faurobert and Albiges-Rizo deals with the molecular mechanisms of CCM disease. By gathering information on the biochemistry and cellular biology of CCM proteins and their partners, it highlights the diverse signaling pathways possibly regulated by these proteins. CCM proteins are likely to assemble into a large intracellular signaling hub that controls endothelial cell–cell junctions, cell shape remodeling and cell adhesion to the extracellular matrix. A global picture remains hard to define, but future findings on CCM will certainly teach us much about blood vessel morphogenesis.
Many new insights have been brought to the CCM research field over the past 2 years. Ongoing studies from very different approaches promise many more surprises and successes for researchers and new hope for patients.
[Eva Faurobert is a CNRS researcher at the Institute Albert Bonniot, Université Joseph Fourier, Grenoble, France. She has previously worked on G-protein signaling in the laboratory of Marc Chabre and Pierre Chardin in Sophia Antipolis, France and during her post-doc in James Hurley's laboratory in Seattle, WA, USA. Two years ago, she joined Corinne Albiges-Rizo's group to focus on the dialogue between the endothelial cell and its extracellular matrix during angiogenesis. Her interest in joining Albiges-Rizo's group was to combine classical cellular biology with animal models and innovative biophysical approaches.]