Pathophysiological effects of calcitonin gene-related peptide in a model of cardiovascular dysfunction and remodelling

Abstract

Hypertension is the number one killer in the Western world at present and is a major risk factor for the development of cardiovascular disease. However, despite the extensive range of therapies, the mechanisms involved in its onset still remain unclear, therefore there is a need to investigate the mechanisms involved. Calcitonin gene-related peptide (CGRP) is best known as a sensory nerve-derived neuropeptide, a potent microvascular vasodilator and is suggested to be protective in a range of models of hypertension. The aim of this study was to investigate the influence of CGRP on vascular mechanisms in an Angiotensin-ll (Ang II) model of hypertension. Wildtype (WT) and aCGRP knockout (aCGRP KO) mice were infused with either vehicle (saline) or Ang II for 14 (1.1mg/kg/day) or 28 (0.9mg/kg/day) days. Under both normal physiological conditions and after saline infusion, blood pressure (BP) and gross pathological observations did not differ between WT and aCGRP KO mice. Ang II infusion caused an increase in BP in the mild-moderate hypertensive range in WT mice at both 14 and 28 days. However in the absence of aCGRP, this hypertension was exacerbated, this being in the moderate hypertensive range at day 14, and becoming severely hypertensive by day 28. When measuring CGRP levels, plasma and mRNA aCGRP expression was upregulated in the aorta and mesenteric vessels of hypertensive WTs, and localisation of CGRP (a and (3) was visible in endothelial and smooth muscle cells of the aorta. This increase in CGRP expression was also accompanied by an increase in CGRP receptor expression at day 28 in WTs. Vascular inflammation/remodelling of the aorta was apparent in the developing hypertension, perhaps via the loss of endothelial derived nitric oxide synthase (eNOS) and a resultant increase in NADPH oxidase. This inflammation/remodelling was characterised by increased luminal wall width, collagen expression and cytokines/adhesion molecules.

Date of Award	2012
Original language	English
Awarding Institution	King's College London
Supervisor	Susan Brain (Supervisor) & Richard Siow (Supervisor)