THE ROLE OF ENDOPLASMIC RETICULUM STRESS IN VASCULAR CALCIFICATION

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Vascular calcification (VC) is a health problem common in ageing
populations, diabetes and chronic kidney disease. It leads to vascular stiffening and heart failure. VC is a regulated process mediated by vascular smooth muscle cells (VSMCs), with similarities to developmental osteogenesis. The exact molecular events responsible for triggering it are unknown. The endoplasmic reticulum (ER) is involved in folding of proteins. ER stress occurs as a result of unfolded protein accumulation and has been implicated in osteoblast differentiation and bone mineralization. Therefore, I hypothesized that ER stress signalling regulates osteogenic differentiation and calcification of VSMCs.
I showed that calcification of human aortas was associated with changes in
ER stress marker expression. Warfarin and TNFα, which are both established
inducers of vascular calcification, increased expression of ER stress markers in
VSMCs. ER stress modelled in human primary VSMCs in vitro increased their
calcification and was shown to modulate expression of a number of bone related
genes, such as BMP-2, Runx2, Osterix, ALP, BSP and OPG in VSMCs in vitro. I also demonstrated that ER stress activated features characteristic of a secretory
phenotype in VSMCs, such as downregulation of SMC markers and components of TGFβ signalling related to contractile differentiation, as well as BMP-2. Taken
together these results suggested that ER stress can induce changes that lead to
osteogenic differentiation.
To further explore the relationship between ER stress and osteogenic
differentiation of VSMCs Osterix and ALP were studied in more detail. ALP activity was upregulated by ER stress, but did not change when VSMCs calcified. Promoter analysis showed that ALP might be regulated by ER stress via indirect mechanisms and potential regulators of ALP transcription were identified using proteomic analysis.
Date of Award2015
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorCathy Shanahan (Supervisor) & Alexander Kapustin (Supervisor)

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