Cerebral cavernous malformations (CCMs) are anomalies of the cerebral vasculature. Loss of the CCM proteins CCM1/KRIT1, CCM2, or CCM3/PDCD10 trigger a MAPK-Kr & uuml;ppel-like factor 2 (KLF2) signaling cascade, which induces a pathophysiological pattern of gene expression. The downstream target genes that are activated by KLF2 are mostly unknown. Here we show that Chromobox Protein Homolog 7 (CBX7), component of the Polycomb Repressive Complex 1, contributes to pathophysiological KLF2 signaling during zebrafish cardiovascular development. CBX7/cbx7a mRNA is strongly upregulated in lesions of CCM patients, and in human, mouse, and zebrafish CCM-deficient endothelial cells. The silencing or pharmacological inhibition of CBX7/Cbx7a suppresses pathological CCM phenotypes in ccm2 zebrafish, CCM2-deficient HUVECs, and in a pre-clinical murine CCM3 disease model. Whole-transcriptome datasets from zebrafish cardiovascular tissues and human endothelial cells reveal a role of CBX7/Cbx7a in the activation of KLF2 target genes including TEK, ANGPT1, WNT9, and endoMT-associated genes. Our findings uncover an intricate interplay in the regulation of Klf2-dependent biomechanical signaling by CBX7 in CCM. This work also provides insights for therapeutic strategies in the pathogenesis of CCM. A novel therapeutic approach for the treatment of cerebral cavernous malformation (CCM) was established through targeting the polycomb repressive complex 1 protein CBX7.In CCM, brain endothelial cells exhibit increased epigenetic modifications due to activity of the polycomb repressive complex 1 protein CBX7.Changes to the epigenetic landscape in affected endothelial cells trigger a pathological gene expression that involves , , , and endoMT genes.The activity of CBX7 is regulated by the transcriptional regulator KLF2 and blood flow.Genetic ablation or pharmacological inhibition of CBX7 in pre-clinical zebrafish, mouse, and human endothelial cell models suppresses cerebral cavernous malformation phenotypes. A novel therapeutic approach for the treatment of cerebral cavernous malformation (CCM) was established through targeting the polycomb repressive complex 1 protein CBX7.