The extracellular-Ca2+ sensing receptor (CaSR) is a G protein-coupled receptor which is essential for Ca2+ homeostasis in the body. The best studied function of the CaSR lies in the parathyroid gland, where hypercalcaemia activates the receptor which in consequence inhibits parathyroid hormone secretion. However, for other tissues like the vasculature the physiological and pathophysiological roles of the CaSR are a lot less well defined. The CaSR is expressed in all layers of blood vessels, the endothelium, the vascular smooth muscle cells (VSMC) and the tunica adventitia. Previous studies have suggested roles for the vascular CaSR in protection against vascular calcification and in blood pressure regulation. In the course of my thesis, I have investigated the specific roles of the vascular CaSR by characterising the phenotype of a transgenic mouse model of targeted CaSR deletion from VSMC (SM22α-Cre x LoxP-CaSR). In characterising this mouse model, I have made three principal discoveries: 1) The VSMC CaSR protects against vascular calcification induced by high Ca2+ and Pi in vitro. No calcification was discovered in mice lacking the VSMC CaSR in vivo, suggesting that this protective effect of the CaSR might only assert itself in pathological disease. 2) The VSMC CaSR contributes to blood pressure regulation. Mice lacking the VSMC CaSR exhibit hypotension which is due to impaired vascular contractility and therefore reduced total peripheral resistance. I propose a role for the VSMC CaSR as auto- / paracrine amplifier of VSMC contraction. Furthermore, knock-out mice exhibit bradycardia and sporadic cardiac remodelling. 3) Mice lacking the VSMC CaSR exhibit profound changes in mineral ion metabolism, together with severe hypercalcaemia, hypercalciuria, hyperphosphaturia and increased 1,25-(OH)2-Vitamin D3 and phosphaturic FGF23 levels, and decreased bone mineral density, consistent with a phenotype resembling primary hyperparathyroidism. The mechanisms behind this influence remain yet to be fully understood.
Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:611042 |
Date | January 2014 |
Creators | Schepelmann, Martin |
Publisher | Cardiff University |
Source Sets | Ethos UK |
Detected Language | English |
Type | Electronic Thesis or Dissertation |
Source | http://orca.cf.ac.uk/60067/ |
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