To determine the temporality of the Rho activation vs. MEKK3 activation, CCM1 depleted EC cells treated with hydroxyfasudil (a Rho inhibitor) was unable to normalize the levels of KLF4/KLF2 while normalized KLF4/KLF2 levels in CCM1 null cells resulted in normal level of Rho activation, suggesting that the KLF4/KLF2 signaling is upstream of the Rho activation in CCM lesions[90]. This evidence concerns the gene KRIT1 and cerebral cavernous malformation.