Ccm2, also known as MGC4607 or malcavernin, is a gene involved in the cerebral cavernous malformation (CCM) signalling pathway. Mutations in Ccm2 lead to CCM, a cerebrovascular disease characterized by the formation of dilated haemorrhagic capillaries in the brain [2,3,4,5,6,7]. Ccm2-related proteins interact with CCM1 and CCM3 to form a ternary cytosolic complex, and are crucial for endothelial cell network formation, cell-cell adhesion, cell shape and polarity, and cell adhesion to the extracellular matrix [3,4,8].

In zebrafish and mouse studies, Ccm2 has been shown to be essential for cardiac development. Endocardial cell-specific deletion of Ccm2 in mice demonstrated its necessity for maintaining the cardiac jelly during early gestation. Genetic deletion of Ccm2 in epicardial cells further revealed that Ccm2 is required by these cells to support heart development. It regulates epicardial cell adhesion, polarity, spreading, and migration. Loss of Ccm2 in epicardial cells delays cardiac function recovery and aggravates cardiac fibrosis following myocardial infarction. Molecularly, Ccm2 targets the production of cytoskeletal and matrix proteins to maintain epicardial cell function [1]. Additionally, in vitro studies on CCM2-silenced endothelial cells showed they enter a senescence-associated secretory phenotype (SASP) driven by ROCK dysfunctions [2].

In conclusion, Ccm2 plays a critical role in both cardiac development and repair, as well as in endothelial cell function. The gene knockout and conditional knockout mouse models have significantly contributed to understanding its functions in these biological processes and in the context of CCM disease. These studies provide insights into the underlying mechanisms and potential therapeutic targets for related cardiovascular and cerebrovascular diseases.