Modulation of vascular tone by neutrophils in vivo

Morton, Jonathan. 2007. Modulation of vascular tone by neutrophils in vivo. PhD Thesis, Cardiff University.

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Abstract

The vascular endothelium regulates vasomotor tone and blood fluidity through the release of paracrine factors, such as nitric oxide (NO). Acutely activated neutrophils have been shown to consume vasodilatory NO in vitro through the NAD(P)H oxidase-dependent generation of superoxide. As such, neutrophils may contribute to the endothelial dysfunction and increased vascular tone commonly observed in inflammatory vascular diseases. Herein, the experiments in this thesis set out to examine a role for neutrophils in the regulation of vascular tone. Initial experiments aimed to assess the capacity of inflammatory-primed neutrophils to consume NO in vitro. Inflammatory priming of human neutrophils resulted in significantly accelerated rates of NO disappearance from aerobic buffer in vitro in an NAD(P)H oxidase-dependent manner. Thus, neutrophil priming may have a detrimental effect on vascular homeostasis in vivo. With this in mind, subsequent chapters aimed to elucidate a role for neutrophils in regulating vascular tone in vivo using immunodepletion techniques. Following neutrophil depletion, mice exhibited a gradual fall in systolic blood pressure over 3 days, and phenylephrine-induced vasoconstriction was significantly attenuated in thoracic aortae isolated from neutropenic animals compared to controls. There effects were due, at least in-part, to the interferon-y-dependent upregulation of inducible nitric oxide synthase (iNOS) bioactivity in the thoracic aortae of neutropenic mice. Thus, under physiological conditions, neutrophils may modulate vascular tone by negatively regulating the bioactivity of pro-inflammatory enzymes, such as iNOS. Finally, the effect of acute neutropenia on angiotensin (Ang) II-induced hypertension in vivo was examined. Neutrophil depletion prevented the onset of Ang II-induced hypertension, indicating that neutrophils may be directly involved in the development of hypertension associated with this octapeptide in vivo. In conclusion, the data described in this thesis highlight the diversity of neutrophil activities in vivo and in vitro and how changes in neutrophil phenotype may impact upon vascular physiology.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
ISBN:	9781303182075
Date of First Compliant Deposit:	30 March 2016
Last Modified:	12 Feb 2016 23:14
URI:	https://orca.cardiff.ac.uk/id/eprint/55681

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