Cerebral arteriovenous malformations (AVMs) are the common vascular malformations that tend to rupture and cause hemorrhagic strokes. Disruptions in the integrity of vascular endothelium and endothelial cell (EC) differentiation give rise to the formation of cerebral AVMs. In previous studies, we reported that endothelial-mesenchymal transitions (EndMTs) contributed to cerebral AVMs in that ECs lost their identity and gained mesenchymal plasticity to cause lumen disorder. We have shown that unwanted induction of Sry-box 2 (Sox2) signaling was responsible for the EndMTs in cerebral AVMs, and identified the beta-adrenergic antagonist pronethalol as an inhibitor of Sox2 expression that stabilized EC differentiation and lumen formation, thereby limiting the cerebral AVMs. We also showed that the depletion of beta-adrenergic receptors had no effect on the Sox2 expression, which suggested that the beta antagonists exerted their effect through other pathways. However, the nature of these pathways remains unclear. Here, we hypothesize that beta-adrenergic antagonist directly inhibits notch-associated transcription factor recombination signal binding protein for immunoglobulin kappa J (RBPJκ), a key component of Notch signaling, to limit induction of Sox2 so as to improve cerebral AVMs. We treated MGP CRISPR cells, in which matrix Gla protein (Mgp) was depleted by using gene-editing tool of clustered regularly interspaced short palindromic repeats and its associated protein 9, with BMP6. We found that BMP6 induced Sox2, Notch1 and Jagged1 and 2. We further performed gene knockdown to reduce RBPJκ and found that the knockdown of RBPJκ abolished the Sox2 induction. We revealed that pronethalol significantly reduced the expression of RBPJκ but did not affect Notch1, Jagged1 or 2. We showed more enriched DNA-binding around the RBPJκ binding site in the Sox2 promoter of the MGP CRISPR cells than control cells. Excess RBPJκ DNA-binding was abolished by treatment of pronethalol in MGP CRISPR cells. Together, the results suggest that the beta antagonists reduce RBPJκ, thereby preventing excess BMP/Notch signaling from inducing Sox2.