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Abstract: FR-PO301

Activation of the IKK2-NFkB Pathway in Vascular Smooth Muscle Cells (VSMCs) Inhibits Vascular Calcification and Stiffness in CKD by Reducing the Secretion of Apoptosis-Mediating Calcifying Extracellular Vesicles

Session Information

Category: Bone and Mineral Metabolism

  • 501 Bone and Mineral Metabolism: Basic


  • Miyazaki, Makoto, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Medial calcification is a major risk factor of cardiovascular mortality, particularly for patients with chronic kidney disease (CKD). IKK2-NFkB pathway mediated-inflammation in vascular smooth muscle cells (VSMCs) has been proposed to be an etiologic factor in vascular calcification. However, the VSMC-specific role of the IKK2-NFkB pathway in vascular calcification remains to be elucidated.


To study the role of the IKK2-NFkB pathway in vascular calcification, we used Cas9-CRISPR and Cre-loxP techniques to delete several key genes in the IKK2-NFkB pathway from cultured VSMCs and mice, respectively.


CKD significantly induced inflammatory factors in VSMCs through activation of the IKK2-NFkB pathway. Unexpectedly, however, CRISPR-mediated knockouts of IKK2, RelA and NFKB1 in VSMCs all exacerbated osteogenic differentiation and mineralization of cultured VSMCs. In vivo studies showed that Cre-mediated VSMC-IKK2 deficiency aggravated vascular calcification and aortic stiffness in CKD mice, whereas the activation of NFkB by VSMC-IkB deficiency attenuated CKD-dependent medial calcification and vascular stiffness. Inhibition of the IKK2-NFkB pathway induced apoptosis of VSMCs in vitro and in vivo by reducing anti-apoptotic gene expression. In addition, increased calcifying extracellular vesicles through the inhibition of the IKK2-NFkB pathway induced mineralization of VSMCs.


Taken together, this study unexpectedly reveals that activation of the IKK2-NFkB pathway in VSMCs plays a protective role in CKD-dependent vascular calcification by reducing the release of apoptotic calcifying extracellular vesicles.


  • NIDDK Support