Regulation of cardiovascular development and integrity by the Heart of Glass-Cerebral Cavernous Malformation pathway

Cerebral cavernous malformations (CCMs) are human vascular malformations caused by mutations in three genes of unknown function, KRIT1, CCM2 and PDCD10. Here we show that the HEG1 receptor, linked to CCM genes in zebrafish, is selectively expressed in endothelial cells and that Heg1(-/-) mice exhibit defective integrity of the heart, blood vessels and lymphatic vessels. In contrast, Heg1(-/-);Ccm2(+/lacZ) and Ccm2(lacZ/lacZ) mice die early in development due to a failure of nascent endothelial cells to associate into patent vessels, a phenotype shared by deficient zebrafish embryos and reproduced by deficient endothelial cells ex vivo. These cardiovascular defects are associated with abnormal endothelial junctions like those observed in human CCMs, and biochemical and cellular imaging studies identify a cell autonomous pathway in which HEG1 receptors couple to KRIT1 at cell junctions. These studies identify HEG1-CCM signaling as a critical regulator of cardiovascular organ formation and integrity.