《cavernous malformations》.pdfVIP

RESEARCH ARTICLE Disease Models Mechanisms 2, 168-177 (2009) doi:10.1242/dmm.001263 Tissue-specific conditional CCM2 knockout mice establish the essential role of endothelial CCM2 in angiogenesis: implications for human cerebral cavernous malformations 1,2 1,2 1,2 3 1 3 Gwénola Boulday , Anne Blécon , Nathalie Petit , Fabrice Chareyre , Luis A. Garcia , Michiko Niwa-Kawakita , Marco Giovannini3 and Elisabeth Tournier-Lasserve1,2,4,* SUMMARY Cerebral cavernous malformations (CCM) are vascular malformations of the brain that lead to cerebral hemorrhages. In 20% of CCM patients, this results from an autosomal dominant condition caused by loss-of-function mutations in one of the three CCM genes. High expression levels of the CCM genes in the neuroepithelium indicate that CCM lesions might be caused by a loss of function of these genes in neural cells rather than in vascular cells. However, their in vivo function, particularly during cerebral angiogenesis, is totally unknown. We developed mice with constitutive and tissue-specific CCM2 deletions to investigate CCM2 function in vivo. Constitutive deletion of CCM2 leads to early embryonic death. Deletion of M CCM2 from neuroglial precursor cells does not lead to cerebrovascular defects, whereas CCM2 is required in endothelial cells for proper vascular M development. Deletion of CCM2 from endothelial cells severely affects angiogenesis, leading to morphogenic defects in the major arterial and D venous blood vessels and in the heart, and results in embryonic lethality at mid-gestation. These findings establish the essential role of endothelial s CCM2 for proper vascular dev