Abstract: SA-PO872

Premature Vascular Smooth Muscle Cell Ageing Drives Inflammation and Calcification in Children on Dialysis

Session Information

  • Vascular Calcification
    November 04, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Mineral Disease

  • 1205 Vascular Calcification

Authors

  • Shanahan, Catherine M., King's College London, London, United Kingdom
  • Sanchis, Pilar, King's College London, London, United Kingdom
  • Liu, Yiwen, King's College London, London, United Kingdom
  • Ho, Chin Yee, King's College London, London, United Kingdom
  • Beltran, Leilani, King's College London, London, United Kingdom
  • Long, David A., University College London, London, United Kingdom
  • Shroff, Rukshana, Great Ormond Street Hospital, London, United Kingdom
Background

Children on dialysis have a cardiovascular mortality risk equivalent to the very elderly in the general population. Medial vascular calcification, an age-associated pathology, is prevalent in these children therefore we investigated whether premature vascular smooth muscle cell (VSMC) ageing might play a role in driving calcification.

Methods

Vessels from children with CKD and controls were harvested at time of surgery and subjected to histological analysis for parameters of ageing. VSMCs grown from these vessels were also phenotyped for calcification propensity and ageing markers including growth capacity, DNA damage, senescence and inflammation. Children with CKD were subjected to vascular phenotyping including pulse wave velocity and spiral CT and these measures were correlated with serum markers of inflammation.

Results

Vessels from children on dialysis showed oxidative DNA damage as well as increased expression of the senescence markers p16 and p21. In vitro VSMCs from dialysis patients showed elevated levels of DNA damage, grew poorly and senesced early compared with control VSMCs. DNA damage correlated with increased expression of the osteogenic markers Runx2 and BMP2, and increased calcification in response to elevated levels of calcium (Ca) and phosphate (P). Ca and P treatment induced oxidative DNA damage in CKD vessel rings ex vivo, and accelerated VSMC senescence in vitro. Cytokine array analysis showed that VSMCs from CKD patients displayed a proinflammatory, senescence associated secretory phenotype (SASP) in vitro, and blockade of ATM-mediated DNA damage signalling reduced inflammation. Clinically, children on dialysis showed elevated circulating levels of SASP factors including BMP2, OPG and IL6 and these correlated with increased vascular stiffening and calcification in vivo.

Conclusion

Taken together, these data suggest that dysregulated mineral metabolism accelerates VSMC ageing by inducing oxidative DNA damage and premature senescence. In turn, the paracrine SASP promotes osteogenic differentiation, vascular calcification and systemic inflammation suggesting drugs that target DNA damage signalling or senolytics may be therapeutic agents for vascular calcification.

Funding

  • Private Foundation Support