Abstract WP435: Endothelium-Specific Sox17 Deletion Ameliorates ALK1-mediated Cerebral Arteriovenous Malformation

    loading  Checking for direct PDF access through Ovid

Abstract

Background and Purpose: 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. The vascular phenomena by endothelial specific deletion of Sox17 and Alk1 are diametrical. Coincidentally, these two antidotal genes act via Notch signaling pathway. Therefore, we hypothesized that deletion of Sox17 in endothelial cells are sufficient to ameliorate brain AVM via Notch pathway modulation.

Methods: Alk12f/2f Sox172f/2f double transgenic mice were bred with VEcad-iCreERT2 mice that express tamoxifen-inducible cre re-combinase in EC. EC-Alk1 and Sox17 deletion was induced by intraperitoneal injection of tamoxifen (25mg/kg) 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 using real-time multiphoton microscopy and immunostaining. EC proliferation and dysplasia index were quantified. The transcripts and protein expression of target molecules of Notch pathway (Dll4, Hey1, Hey2, NIICD) were also evaluated.

Results: The dysplastic blood vessel index of solitary Alk12f/2f deletion mice was higher than Alk12f/2f-Sox172f/2f double transgenic mice (P<0.001). Dysplasia in Alk12f/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.

Related Topics

    loading  Loading Related Articles