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Title: Calcitonin gene-related peptide (CGRP) in age-associated vascular inflammation and leukocyte trafficking
Author: King, Ross
ISNI:       0000 0004 5368 2930
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2015
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Calcitonin gene-related peptide (CGRP) is a 37 amino acid neuropeptide that is predominantly synthesised and secreted by small, thinly-myelinated and unmyelinated sensory neurons that richly innervate the vasculature. It is perhaps best known for its ability to act as a potent dilator of the microvasculature and its role as a vasculoprotectant is gradually being discovered within a range of cardiovascular disease models. However, the role of CGRP in the ageing cardiovascular system and current information regarding CGRP and the ageing process in general is unknown. This study is particularly relevant as ageing is the single biggest independent risk factor for the development of future cardiovascular complications. We hypothesised that CGRP may have a beneficial role in protecting the cardiovascular system against age-associated cardiovascular disease, such as hypertension, and related vascular inflammatory processes mediated by aberrant inflammatory cell activity. We initially characterised the vascular phenotype of ageing (15 months) αCGRP wild type (WT) and knockout (KO) mice, in comparison to respective juveniles (3 months). We found that aged animals had comparable blood pressures to juvenile animals and KO mice did not differ significantly from WTs at either timepoint. Furthermore, markers of leukocytic vascular inflammation were significantly raised within the aortae of ageing mice but the genetic deletion of αCGRP had no bearing on this process. To study direct influences of CGRP on inflammatory processes driven by leukocytes, we employed a reductive approach and studied leukocyte-endothelial cell interactions in vitro, under physiological flow conditions. Here, we showed that treatment of endothelial cells with CGRP for six hours is sufficient to attenuate the adhesion of monocytic cells to tumour necrosis factor alpha (TNFα)-activated HUVEC (HUVEC) by around 50%. The mechanisms regulating this phenomenon did not appear to be related to alterations in the whole-cell expression of classical cell adhesion molecules, including vascular cell adhesion molecule-1(VCAM-1). Furthermore, microarray analysis of HUVEC transcriptome revealed that CGRP did not influence gene expression induced by TNFα in these cells. We finally sought to establish a novel geriatric pathology model in mice that may be more relevant to the human disease condition. To do this, we infused aged αCGRP WT and KO mice with 1.1 mg/kg/day angiotensin II (ATII) for 14 days to induce hypertension and vascular inflammation. However, despite some level of pharmacological activity by ATII, we did not witness the induction of hypertension and we observed no clear vascular inflammatory phenotype. This thesis provides evidence that ageing in mice is sufficient to induce vascular inflammation in the absence of an overt maladaptive cardiovascular phenotype, where the deletion of αCGRP appears to have minimal effect. However, we have uncovered novel evidence to suggest that CGRP might be protective against leukocytic inflammation by virtue of its ability to attenuate leukocyte-endothelial cell interactions under physiological flow conditions.
Supervisor: Ivetic, Aleksandar ; Brain, Susan Diana Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available