Signalling switches maintain intercellular communication in the vascular endothelium

Abstract

Background and purpose: The single layer of cells lining all blood vessels, the endothelium, is a sophisticated signal co-ordination centre that controls a wide range of vascular functions including the regulation of blood pressure and blood flow. To co-ordinate activities, communication among cells is required for tissue level responses to emerge. While a significant form of communication occurs by the propagation of signals between cells, the mechanism of propagation in the intact endothelium is unresolved.

Experimental approach: Precision signal generation and targeted cellular manipulation was used in conjunction with high spatiotemporal mesoscale Ca²⁺ imaging in the endothelium of intact blood vessels.

Key results: Multiple mechanisms maintain communication so that Ca²⁺ wave propagation occurs irrespective of the status of connectivity among cells. Between adjoining cells, regenerative IP₃-induced IP₃ production transmits Ca²⁺ signals and explains the propagated vasodilation that underlies the increased blood flow accompanying tissue activity. The inositide is itself sufficient to evoke regenerative phospholipase C-dependent Ca²⁺ waves across coupled cells. None of gap junctions, Ca²⁺ diffusion or the release of extracellular messengers is required to support this type of intercellular Ca²⁺ signalling. In contrast, when discontinuities exist between cells, ATP released as a diffusible extracellular messenger transmits Ca²⁺ signals across the discontinuity and drives propagated vasodilation.

Conclusion and implications: These results show that signalling switches underlie endothelial cell-to-cell signal transmission and reveal how communication is maintained in the face of endothelial damage. The findings provide a new framework for understanding wave propagation and cell signalling in the endothelium.

Keywords: blood vessels; calcium signalling; calcium waves; cell communication; endothelium; vascular tone.