Pressure-dependent regulation of Ca2+ signaling in the vascular endothelium

Calum Wilson, Christopher D. Saunter, John M. Girkin, John G. McCarron

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

The endothelium is an interconnected network upon which hemodynamic mechanical forces act to control vascular tone and remodeling in disease. Ca2+ signaling is central to the endothelium's mechanotransduction and networked activity. However, challenges in imaging Ca2+ in large numbers of endothelial cells under conditions that preserve the intact physical configuration of pressurized arteries have limited progress in understanding how pressure-dependent mechanical forces alter networked Ca2+ signaling. We developed a miniature wide-field, gradient-index (GRIN) optical probe designed to fit inside an intact pressurized artery which permitted Ca2+ signals to be imaged with subcellular resolution in a large number (∼200) of naturally-connected endothelial cells at various pressures. Chemical (acetylcholine) activation triggered spatiotemporally-complex, propagating IP3-mediated Ca2+ waves that originated in clusters of cells and progressed from there across the endothelium. Mechanical stimulation of the artery, by increased intraluminal pressure, flattened the endothelial cells and suppressed IP3-mediated Ca2+ signals in all activated cells. By computationally modeling Ca2+ release, endothelial shape changes were shown to alter the geometry of the Ca2+ diffusive environment near IP3 receptor microdomains to limit IP3-mediated Ca2+ signals as pressure increased. Changes in cell shape produce a geometric, microdomain-regulation of IP3-mediated Ca2+ signaling to explain macroscopic pressure-dependent, endothelial-mechanosensing without the need for a conventional mechanoreceptor. The suppression of IP3-mediated Ca2+ signaling may explain the decrease in endothelial activity as pressure increases. GRIN imaging provides a convenient method that provides access to hundreds of endothelial cells in intact arteries in physiological configuration.
LanguageEnglish
Pages5231-5253
Number of pages23
JournalJournal of Physiology
Volume593
Issue number24
Early online date28 Oct 2015
DOIs
Publication statusPublished - 15 Dec 2015

Fingerprint

Vascular Endothelium
Endothelial cells
Pressure
Endothelial Cells
Arteries
Endothelium
Inositol 1,4,5-Trisphosphate Receptors
Imaging techniques
Mechanoreceptors
Cell Shape
Hemodynamics
Acetylcholine
Chemical activation
Cells
Geometry

Keywords

  • pressure-dependent Ca2+
  • Ca2+ signaling
  • imaging
  • endothelium

Cite this

Wilson, Calum ; Saunter, Christopher D. ; Girkin, John M. ; McCarron, John G. / Pressure-dependent regulation of Ca2+ signaling in the vascular endothelium. In: Journal of Physiology. 2015 ; Vol. 593, No. 24. pp. 5231-5253.
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Pressure-dependent regulation of Ca2+ signaling in the vascular endothelium. / Wilson, Calum; Saunter, Christopher D.; Girkin, John M.; McCarron, John G.

In: Journal of Physiology, Vol. 593, No. 24, 15.12.2015, p. 5231-5253.

Research output: Contribution to journalArticle

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