Calcium Signalling in the Endothelium and its Control Over Vascular Tone in Health and Obesity

  • Mariam Alakrawi

Student thesis: Phd

Abstract

Obesity is a major medical concern and remains a critical unsolved global health issue. It is associated with many life- threating diseases including cerebral, cardiovascular and microvascular complications. Microcirculation controls blood flow and vascular tone, and in small resistance arteries, the main mechanism of vasodilation is through EDH which is tightly regulated by local Ca2+ signals. There is considerable evidence linking obesity with defects in the Ca2+ signalling and the downstream KCa channels during EDH which cause small artery dysfunction. Obesity-induced disruption of Ca2+ signalling mechanisms remain elusive, and little is known about the exact underlying abnormality in human obesity as it is only beginning to emerge. Thus, it is important to address two major aspects related to vascular health in obesity including Ca2+ signalling and arterial vasodilation function. This study aimed at identifying endothelial and VSMC local Ca2+ signals influencing small arteries vasodilation function in human obesity. To investigate underlying mechanisms small artery’s vasodilatory local Ca2+ signalling, and functional vasodilation were studied in a human model of obesity. Isolated omental small arteries were examined using high speed spinning disc confocal microscopy in order to image intracellular Ca2+ signalling in the endothelium and VSMC. Wall tension recording using wire myography was also utilized to assess wire-induced stretch and agonist effects. Results of this study have shown that TRPV4 mediates vasodilation in human omental arteries via VSMC mechanism and that the endothelium is essential regulatory element in the control of TRPV4-mediated relaxation. Also, results have shown that Ca2+ signalling in the endothelium and VSMC as well as small arteries vasodilation are preserved in human obesity. Neither the function nor cellular components of small omental arteries were affected by obesity. Collectively, our findings provide a highly integrated cellular model through which the interplay among IKCa /SKCa and BKCa channels is governed by Ca2+ signals during TRPV4 channel activation. The manipulation of TRPV4 signalling represents a promising strategic target in the evaluation of new protective therapeutics to defend small arteries against obesity’s adverse complications. 'See full text for abstract.'
Date of Award31 Dec 2021
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorAlison Gurney (Supervisor) & Adam Greenstein (Supervisor)

Keywords

  • Endothelium
  • TRPV4
  • Obesity
  • Ca2+ signalling

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