Abstract 125: Increased Endothelial Endoglin Gene Deletion and Co-deletion of EphrinB2 Enhance Brain Arteriovenous Malformation in Mice
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.
Author Disclosures: R. Zhang: None. W. Zhu: None. L. Ma: None. M. Luo: None. L. Zhan: None. H. Su: None.
- © 2017 by American Heart Association, Inc.