Heterogeneity in the vascular endothelium enables parallel processing of multiple stimuli

Student thesis: Doctoral Thesis

Abstract

The endothelium is a complex network of cells that lines the entire vasculature and it controls virtually all cardiovascular functions. Changes in the behaviour of endothelial cells underly almost all cardiovascular disease. To regulate cardiovascular function, the endothelium integrates hundreds of signals that provide constant instructions. Signals arrive from as close as neighbouring endothelial cells and underlying smooth muscle cells to substances circulating from the most remote outpost of the body. These signals provide endless streams of information that must be integrated and decoded. How this is achieved is not understood. Therefore, the aim of this thesis is to investigate the mechanisms involved in endothelial Ca2+ signalling to muscarinic, purinergic and histaminergic activators and how the endothelium manages these extracellular signals when multiple agonists are present.Using en face artery preparations we recorded the concurrent Ca2+ activity from hundreds of endothelial cells in intact resistance arteries. The results show that the endothelium is not a homogenous population of cells. Instead, spatially-distinct endothelial cells are primed to detect specific extracellular signals. These spatially distinct cells are arranged in clusters and there is minimal overlap in agonist sensitivity between various clusters. By organising distinct subpopulations of cells to detect specific extracellular signals, the endothelium is able to carry out multiple, completely separate, functions in parallel. In response to each type of extracellular signal, cells generate intracellular messages that have unique characteristics.When multiple extracellular signals are present together, messages are communicated across cells and computations carried out to generate new signals that are a composite of the inputs. These results suggest individual endothelial cells communicate with their neighbours and complex computations are carried out by combining the information from each source to generate a distinct output. These emergent properties of the endothelium generatea system in which the whole is not equal to the sum of the individual parts. This thesis also describes an inexpensive and flexible pressure myograph system, VasoTracker, which permits the vascular activity of isolated, pressurized bloodvessels to be monitored. The system includes all components that would be expected from a commercial pressure myograph system. VasoTracker is an open source system that makes use of existing hardware and software open source solutions.
Date of Award28 Jul 2020
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsUniversity of Strathclyde
SupervisorJohn McCarron (Supervisor) & Calum Wilson (Supervisor)

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