Ccm1 regulates microvascular morphogenesis during angiogenesis.

Cerebral cavernous malformations (CCMs) are characterized by abnormally dilated intracranial capillaries that have a propensity to bleed. The development of some CCMs in humans has been attributed to mutations in CCM1 and CCM2 genes. In animal models, major cardiovascular defects caused by both gene mutations have been observed. However, the effects of the loss of Ccm function on the microvasculature in animal models are less defined. Using high-resolution imaging in vivo, we demonstrated that the loss of Ccm1 in zebrafish embryos leads to failed microvascular lumenization during angiogenesis due to impaired intraendothelial vacuole formation and fusion. No developmental changes during vasculogenesis and the initial stage of angiogenesis were observed, being in contrast to prior reports. In vivo zebrafish studies were further substantiated by in vitro findings in human endothelial cells that elucidated the biochemical pathways of CCM1 deficiency. We found that CCM1 regulates angiogenic microvascular lumen formation through Rac1 small GTPase. In summary, Ccm1 has been identified as a key angiogenic modulator in microvascular tubulogenesis. Additionally, the microvascular pathology observed in developing Ccm1 mutant zebrafish embryos mirrors that seen in human CCM lesions, suggesting that zebrafish might provide a superior animal model to study the pathogenesis of human CCM.