The role of inflammatory chemokine receptors in hypertension and blood pressure regulation

Vidler, Francesca (2020) The role of inflammatory chemokine receptors in hypertension and blood pressure regulation. PhD thesis, University of Glasgow.

Abstract

Chemokines regulate the migration of leukocytes through binding to chemokine receptors. The inflammatory CC chemokine receptors CCR1, CCR2, CCR3 and CCR5 (iCCRs) are expressed by several different leukocytes and are important in orchestrating inflammatory responses. These receptors can bind to multiple CC chemokines and many of these chemokines share receptors, resulting in a highly complex system in which the exact role of each receptor is not understood. To aid understanding of these receptors, two unique mouse strains have been developed. These are mice that are deficient for all four iCCRs (iCCR-KO) and mice that express fluorescent reporter proteins for each of the iCCRs (REP mice).

Hypertension is when blood pressure (BP) is elevated above 140/90 mmHg. There is evidence for a role of inflammation in the development of hypertension and the consequent end organ damage which increases the risk of cardiovascular disease. Several chemokines and chemokine receptors have been implicated in hypertension but due to the complexity of the chemokine system, the role they play in the pathogenesis of the disease is unclear. Therefore the role of iCCRs in hypertension was investigated using iCCR-KO and REP mice.

WT, REP and iCCR-KO mice were subject to 7 or 14 days of Angiotensin (Ang) II induced hypertension. iCCR expression was characterised in REP and WT mice and the effect of iCCR deficiency on BP, vascular function, inflammation and cardiac and vascular remodelling was assessed using the iCCR-KO mice. Aortic CCR2 and CCR5 expression increased in Ang II treated WT mice compared to control WT mice. Further, iCCR-KO mice were protected from Ang II induced vascular dysfunction but iCCR deficiency did not influence BP or remodelling. iCCR-KO mice were also shown to have altered circulating leukocyte populations in Ang II induced hypertension.

Control iCCR-KO mice tended to have a lower BP than WT mice so the effect of iCCR deficiency on regulators of BP in the kidneys and kidney leukocyte infiltration was investigated. iCCR-KO mice had fewer inflammatory monocytes and reduced mineralocorticoid receptor mRNA expression. This could influence BP but further studies are needed.

Overall, novel mouse models have been used to identify how iCCRs are involved in hypertension. The results described here suggest that iCCRs, in particular CCR2 and CCR5, are involved in regulating vascular dysfunction in hypertension. Through improving understanding of these receptors in the disease, there is increased potential to target them as treatments that would ultimately reduce the risk of cardiovascular disease.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Hypertension, chemokines, chemokine receptors, inflammation, blood pressure
• Subjects: Q Science > QR Microbiology > QR180 Immunology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Immunology & Infection
• Supervisor's Name: Graham, Professor Gerard
• Date of Award: 2020
• Depositing User: Miss Francesca Vidler
• Unique ID: glathesis:2020-79045
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 02 Mar 2020 17:00
• Last Modified: 27 May 2021 09:14
• Thesis DOI: 10.5525/gla.thesis.79045
• URI: https://theses.gla.ac.uk/id/eprint/79045