DPDH prevents cerebral cavernous malformation progression

ABSTRACT: Cerebral cavernous malformations (CCMs) are deemed to be common neurovascular dysplasias that are prone to hemorrhage characterized by abnormal activation of MEKK3. Current understanding of precise effects of MEKK3 on governing the transformation from initial lesions into mature and active lesions in CCMs is far from complete and whether MEKK3 could serve as a reliable target for hindering the development of CCMs still remain unclarified. In this study, we demonstrate a prominent reduction in light of the number and size of vascular lesions in the hindbrains of iECre;Krit1fl/fl;Mekk3fl/+ mice compared to that of iECre;Krit1fl/fl mice, indicating that activation of MEKK3 signaling in the endothelium yields CCM lesions, which is consistent with previous findings. More interestingly, our data further unveil that MEKK3 signaling in the microglial cells that are recruited by fibrinogen exacerbates the lesions at the late stage of CCM progression. Mechanistically, aberrant activation of MEKK3 on endothelial cells (ECs) is inclined to disrupt the endothelial junctions via regulating the MEKK3-KLF2/4 signaling axis. Meanwhile, the recruited microglial cells can phagocytize ECs by virtue of the MEKK3-NFκB signaling cascade. Therefore, manipulation of MEKK3 on both ECs and microglial cells may emerge as an effective and efficient therapeutic strategy for retarding the progression of CCMs. Leveraging artificial intelligence-assisted drug design and structural modification, we identified (R)-1,6-dimethyl-11-phenyl-1,10-dihydro-2H-furo[2',3':1,2]phenanthrol[3,4-d]imidazole (DPDH) as an optimal small-molecule inhibitor of MEKK3 enzyme activity. To better explore the underlying mechanisms of DPDH retarding the progression of CCM lesions, we thus carried out the RNA-seq to examine the transcriptome of ECs isolated from the cerebella of P19 Krit1iECKO mice in the absence or presence of DPDH treatment

ORGANISM(S): Mus musculus

PROVIDER: GSE303628 | GEO | 2026/07/24

REPOSITORIES: GEO