Regulation of cardiovascular development and integrity by the heart of glass–cerebral cavernous malformation protein pathway

Abstract

Cerebral cavernous malformation (CCM) is a life-threatening disorder in which blood vessels in the brain dilate and frequently hemorrhage. Benjamin Kleaveland et al. now provide evidence that CCM arises from defects in a signaling pathway involving the KRIT1 and CCM2 intracellular proteins (which have been previously implicated in CCM) and the HEG1 receptor; this pathway acts in endothelial cells and is required for vascular integrity. The role of the CCM2 protein in the endothelium is also explored in another paper published in this issue of Nature Medicine, by Kevin Whitehead et al. 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 heart of glass (HEG1) receptor, which in zebrafish has been linked to ccm gene function, is selectively expressed in endothelial cells. Heg1−/− mice showed defective integrity of the heart, blood vessels and lymphatic vessels. Heg1−/−; Ccm2lacZ/+ and Ccm2lacZ/lacZ mice had more severe cardiovascular defects and died early in development owing to a failure of nascent endothelial cells to associate into patent vessels. This endothelial cell phenotype was shared by zebrafish embryos deficient in heg, krit1 or ccm2 and reproduced in CCM2-deficient human endothelial cells in vitro. Defects in the hearts of zebrafish lacking heg or ccm2, in the aortas of early mouse embryos lacking CCM2 and in the lymphatic vessels of neonatal mice lacking HEG1 were associated with abnormal endothelial cell junctions like those observed in human CCMs. Biochemical and cellular imaging analyses identified a cell-autonomous pathway in which the HEG1 receptor couples to KRIT1 at these cell junctions. This study identifies HEG1-CCM protein signaling as a crucial regulator of heart and vessel formation and integrity.