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Abstract: PO0322

Impaired Arterial Vitamin D Signaling Is Pathogenic in Vascular Calcification

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Lim, Kenneth, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Molostvov, Guerman, University of Birmingham, Birmingham, United Kingdom
  • Lubczanska-Hadley, Maria Anna, University of Warwick, Coventry, United Kingdom
  • Fletcher, Simon, University Hospital Coventry and Warwickshire, Coventry, United Kingdom
  • Bland, Rosemary, University of Warwick, Coventry, United Kingdom
  • Hiemstra, Thomas F., University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
  • Zehnder, Daniel, North Cumbria Integrated Care University Hospital NHS Trust, Carlisle, United Kingdom
Background

Conflicting data exists as to whether vitamin D receptor agonists (VDRa) are protective of arterial calcification. This is confounded by inherent physiological differences between human and animal experimental models and conflicting published data. Herein, the study aims to address these problems by leveraging frontiers in human arterial organ culture models.

Methods

Human arteries were collected from 24 patients (healthy controls, n=12; end-stage CKD, n=12). Cross-sectional and interventional studies were performed using arterial organ cultures treated with normal and calcifying (containing 5mmol/L CaCl2 and 5mmol/L b-glycerophosphate) medium, ex vivo. To assess the role of VDRa therapy, arteries were treated with either calcitriol or paricalcitol.

Results

Human arteries express a functionally active vitamin D system, including VDR, 1α-hydroxylase and 24-hydroxylase (24-OHase) components and these were dysregulated in CKD arteries. Arteries from CKD patients exhibited reduced capacity to synthesize 1,25(OH)2D, increased basal expression and excessive induction of the vitamin D catabolic pathway in response to VDRa. VDRa therapy increased VDR expression in healthy (p<0.01) but not CKD arteries. VDRa treatment suppressed Runx2 and MMP-9 expression in CKD arteries, however only paricalcitol suppressed MMP-2. VDRa exposure did not modulate arterial calcification in all organ culture models. However, VDRa reduced senescence associated β-galactosidase (SAβG) staining in human aortic-smooth muscle cells under calcifying conditions, in vitro.

Conclusion

Maladaptation of arterial vitamin D signaling components occurs in CKD. VDRa exposure can exert vasculo-protective effects and seems critical for the regulation of arterial health in CKD.

Funding

  • NIDDK Support