Cerebral cavernous malformations (CCMs) are common vascular abnormalities that are caused by mutations in CCM1, CCM2, or CCM3 genes. A complex containing the proteins encoded by these genes mediates signaling from the heart of glass (HEG) transmembrane receptor to intracellular stress response pathways involving Rho family guanine triphosphatases (GTPases) and c-Jun N-terminal kinase (JNK). However, CCM genes are expressed in various tissues besides endothelium, generating controversy over whether these genes act in an endothelial cell–autonomous or –nonautonomous manner. Now, two groups have independently demonstrated that CCM2 functions in endothelial cells during angiogenesis. Whitehead et al. observed embryonic lethality due to vascular defects in mice that were globally homozygous for a null allele of CCM2, phenotypes that were also seen in mice with a conditional ablation of CCM2 in endothelial cells, but not in neurons or in smooth muscle cells. In three-dimensional culture, endothelial cells form tube-like structures, a process that requires them to migrate, sprout, and develop a lumen through the fusion of intracellular vacuoles. siRNA knockdown of CCM2 in human umbilical vein endothelial cells prevented lumen formation, which the authors attributed to defects in endothelial cell vacuolation. In addition, human microvascular endothelial cells deficient in CCM2 displayed increased stress fiber formation and impaired barrier formation, as well as higher amounts of activated RhoA GTPase and phosphorylated JNK. Inhibition of RhoA by simvastatin reduced stress fiber formation and JNK phosphorylation in CCM2-deficient cells and reversed permeability increases caused by vascular endothelial growth factor in mice that were heterozygous for the null allele of CCM2. In the paired paper, Kleaveland et al. investigated the signaling pathway mediated by CCM2 and the HEG receptor. Mice lacking Heg1 displayed defects in myocardial formation and in heart, blood vessel, and lymphatic vessel integrity. Heg1-null mice that were also heterozygous or homozygous for a null allele of CCM2 did not develop functional circulatory systems due to deficiencies in vessel lumen formation, and similar phenotypes were observed in zebrafish injected with antisense morpholinos against heg or ccm2. However, Kleaveland et al. found that CCM2 deficiency affected lumen formation by impairing endothelial cell junction formation, rather than endothelial cell vacuolation as observed by Whitehead et al. In the associated commentary, Patterson notes that these conflicting findings about the mechanism by which CCM2 affects angiogenesis must be resolved to develop effective therapies targeting the CCM signaling pathway.
B. Kleaveland, X. Zheng, J. J. Liu, Y. Blum, J. J. Tung, Z. Zou, M. Chen, L. Guo, M.-m. Lu, D. Zhou, J. Kitajewski, M. Affolter, M. H. Ginsberg, M. L. Kahn, Regulation of cardiovascular development and integrity by the heart of glass–cerebral cavernous malformation protein pathway. Nat. Med. 15, 169–176 (2009). [PubMed]
K. J. Whitehead, A. C. Chan, S. Navankasattusas, W. Koh, N. R. London, J. Ling, A. H. Mayo, S. G. Drakos, D. A. Marchuk, G. E. Davis, D. Y. Li, The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases. Nat. Med. 15, 177–184 (2009). [PubMed]
C. Patterson, Torturing a blood vessel. Nat. Med. 15, 137–138 (2009). [PubMed]