Abstract 13571: Endothelial Jagged1 in Vascular Calcification Induced by Chronic Kidney Disease

Abstract

Introduction: Chronic kidney disease (CKD)-induced vascular calcification (VC) is a dire complication with high incidence, while its pathogenesis has not been fully elucidated. Hypothesis: We hypothesized that endothelial Jagged1 prevents vascular smooth muscle cell from osteoblast trans-differentiation thus alleviates CKD induced vascular calcification. Methods: We have generated a CKD mouse model by 5/6 nephrectomy followed by high phosphate diet (HPiD). CKD-induced VC were determined in Jagged1 EC specific KO and Notch3 KO mice. Co-culture of EC with vascular muscle cells (VSMCs) was performed to study the mechanism. Results: Endothelial Jagged1 expression was decreased in calcified arteries from CKD patients vs . normal arteries. Knockout of EC Jagged1 significantly induced artery calcification and decreased the mice survival rate vs. WT CKD mice. There was decreased expression of VSMC contractile markers and Notch3, and increased expression of ossification markers in calcified arteries from endothelial Jagged1 KO CKD mice. Furthermore, overexpression of EC Jagged1 significantly prevented artery calcification. In EC Jag1 OE /Notch3 KO CKD mice, KO Notch3 partially blocked the protective effects on VC by Jag1 OE. In co-culture experiments, KO of Jagged1 in ECs enhanced transdifferentiation of VSMCs into osteoblast cells after high-phosphate (HPi) treatment, while overexpression of Notch3 alleviated calcium deposition induced by HPi. Silencing Hes1 in VSMC led to remarkably increased Runx2 expression and more severe calcification in response to HPi treatment. Conclusions: Jagged1 expression in ECs controls CKD-induced VC. Down-regulation of EC Jagged1 impairs VSMC Notch3 activation, thus induces VSMC transdifferentiation and VC through Notch target Hes1.