Abstract 125: Increased Endothelial Endoglin Gene Deletion and Co-deletion of EphrinB2 Enhance Brain Arteriovenous Malformation in Mice

Abstract

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 ( Eng 2f/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.