HES1 and cerebral cavernous malformation: A dramatic down-regulation of the target gene HEY2 and HES1 was also observed in Mu-CCM3, indicating an impaired DLL4-Notch signalling in familial CCM with germline mutation in CCM3. Interestingly, the level of Notch1 was similarly detected in Mu-CCM3 and in Sp-CCMs (Fig. 3A).