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Introduction:Endoglin (Eng) is an arteriovenous malformation (AVM) causative gene. In adult mice, global Eng deletion induced by a wild-type cre (cre) results in AVM formation in the brain angiogenic region. We hypothesize that using a codon-improved cre (icre) to increase Eng gene deletion in endothelial cells and co-deletion of the EphrinB2 gene, a determinant of arterial endothelial differentiation, will enhance brain AVM severity.Methods:Eng was globally deleted in adult Eng-floxed mice (Eng2f/2f) using a rosa promoter driving estrogen inducible cre (Rosa-creER), or in endothelial cells using a platelet-derived growth factor b promoter driving estrogen inducible icre (pdgfb-icreER). Pdgfb-icreER was also used to mediate endothelial deletion of EphrinB2. An adeno-associated viral vector expressing vascular endothelial growth factor was injected into the brain to induce brain angiogenesis.Results: Compared with Rosa-CreER-mediated global Eng deletion, pdgfb-icreER-induced endothelial Eng deletion did not increase the number of abnormal vessels (P=0.39), but reduced vascular smooth muscle coverage (P=0.03) and increased hemorrhage (P=0.04) in the brain AVM lesion. Additional endothelial deletion of EphrinB2 gene increased the number of abnormal vessels in the brain (P=0.08).Conclusion: These data indicate that a positive correlation exists between the degree of gene mutation in the endothelial cells and brain AVM severity, and that dysregulation of endothelial arteriovenous specification enhances AVM formation and progression.