Abstract WP333: Endothelium-Specific Sox17 Deletion Ameliorates ALK1-mediated Arteriovenous Malformation (AVM)

Abstract

Introduction: Sox17 promotes endothelial migration by destabilizing endothelial adherens junctions, rearranging cytoskeletal structure and upregulates expression of a number of genes preferentially expressed in angiogenic tip cells. However, the deletion of Sox17 stabilizes endothelial junctions and decreased proliferation, vice versa. The AVM after endothelial Alk1 deletion shows uncontrolled endothelial proliferation and cytoskeletal misarrangement. Therefore, we hypothesized that deletion of Sox17 in endothelial cells are sufficient to ameliorate brain AVM via Notch pathway modulation. Methods: Alk1 2f/2f Sox17 2f/2f double transgenic mice (Alk1 exons 4-6 flanked by loxP sites) were bred with VEcad-iCreER T2 mice that express tamoxifen-inducible cre re-combinase (iCreER) in EC. EC-Alk1 and Sox17 deletion was induced by intraperitoneal injection of tamoxifen (25mg/kg, Sigma-Aldrich) with interval of 3 days. The spatiotemporal changes of blood vessel were investigated in Alk1 deletion alone and Alk1-Sox17 co-deletion mice. Vascular morphology was analyzed 9 days after tamoxifen administration. The transcripts (mRNA) and protein expression of target molecules of Notch pathway (Dll4, Hey1, Hey2, NIICD) were also evaluated. Results: The dysplastic blood vessel index of solitary Alk1 2f/2f deletion mice was higher than Alk1 2f/2f -Sox17 2f/2f double transgenic mice (P<0.001) and was similar to human AVM. Dysplasia in Alk1 2f/2f mice was partially rescued by Sox17 co-deletion in morphologically. In addition, target molecules of Notch pathway, Dll4, Hey1, Hey2, Jag1 was increased in Alk1-Sox17 co-deletion mice rather than solitary Alk1 deletion mice. Conclusions: Collectively, our findings demonstrate that the modulation of Sox17 could restrict the Alk1-induced AVM by upregulation of Notch pathway. This work establishes the Notch-Sox17 axis as a novel regulatory mechanism underlying Notch-mediated vascular stabilization in brain AVM.