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Investigating the role of the YEARextracellular calcium-sensing receptor(CaSR) in vascular pathophysiology using a novel mouse model of selective ablation of CaSR from mouse vascular smooth muscle cells

Davies, Thomas 2013. Investigating the role of the YEARextracellular calcium-sensing receptor(CaSR) in vascular pathophysiology using a novel mouse model of selective ablation of CaSR from mouse vascular smooth muscle cells. PhD Thesis, Cardiff University.
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Abstract

The extracellular calcium-sensing receptor (CaSR) is a G-protein coupled receptor central to systemic Ca2+ homeostasis in mammals. We have previously shown that CaSR is expressed in primary bovine aortic vascular smooth muscle cells (VSMCs). Furthermore, dominant-negative adenoviral knockdown of this receptor in bovine VSMCs in vitro causes enhanced calcification in the presence of culture conditions which mimic vascular calcification in vivo. Using mineralising conditions in vitro, we have also previously demonstrated that positive pharmacological allosteric activation of CaSR using the calcimimetic, R-568, significantly reduces calcification of bovine VSMCs. These findings now implicate the CaSR, not just in systemic Ca2+ homeostasis, but also in potential protection against vascular calcification; a condition associated with increased blood pressure, left ventricular hypertrophy, chronic kidney disease and cardiovascular morbidity. Using a specific targeted deletion strategy, we have developed CaSR-specific knockout in VSMCs driven by the SM22α promoter. Using in vitro, ex vivo and in vivo approaches, here, I have characterised the cardiovascular phenotype of this novel transgenic mouse model. In vivo data demonstrate that ablation of CaSR from VSMCs causes hyperkalaemia at 3 months of age and hypercalcaemia throughout life. 3 month old CaSR-VSMC Knockout (KO) mice also exhibit reduced bone mineral integrity and increased heart weight at the age of 18 months. Ex vivo analysis implicates the VSMC-CaSR as a modulator of blood vessel tone. CaSR-VSMC KO mice exhibit reduced luminal diameters of the aorta and mesenteric arteries. CaSR-VSMC KO also reduces contractile tone in addition to evoking Ca2+-dependent relaxation only, compared to CaSR-wild-type (WT) mice which exhibit both Ca2+-dependent contraction and relaxation of the aorta. In vitro analyses confirm that CaSR expression and activation reduces Ca2+-dependent proliferation and mineralisation. In conclusion, the VSMC CaSR is a modulator of vascular tone ex vivo and of VSMC proliferation and calcification in vitro.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Biosciences
Subjects: Q Science > QH Natural history > QH301 Biology
Q Science > QP Physiology
Uncontrolled Keywords: Vascular Calcification ; Calcium Sensing Receptor ; Smooth Muscle Cell
Funders: BBSRC, Amgen Inc.
Date of First Compliant Deposit: 30 March 2016
Last Modified: 28 Jun 2019 03:23
URI: http://orca.cardiff.ac.uk/id/eprint/47503

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