Inside-out IP3-mediated G protein-coupled receptor activation drives intercellular Ca2+ signaling in the vascular endothelium

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Buckley, C. and Zhang, X. and Lee, M. D. and Wilson, C. and McCarron, J. G. (2025) Inside-out IP3-mediated G protein-coupled receptor activation drives intercellular Ca2+ signaling in the vascular endothelium. FASEB Journal, 39 (14). e70818. ISSN 0892-6638 (https://doi.org/10.1096/fj.202500370RR)

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Abstract

The endothelium's control of nearly all vascular function relies on rapid intercellular communication to coordinate cellular activity across scale. A key form of intercellular communication arises from the regenerative propagation of IP3-evoked Ca2+ signals from cell to cell, which regulate vessel tone, modulate vascular permeability, and determine immune responses. Despite their importance, the mechanisms by which regenerative propagation of IP3-evoked Ca2+ signals occurs are poorly understood. Here, in intact resistance arteries, precision photolysis of IP3 combined with high-resolution mesoscale imaging, targeted drug application, and advanced analytical techniques was used to determine the mechanisms underlying regenerative propagation of IP3-evoked Ca2+ signals in the endothelium. Elevated IP3 in the initiating cell triggers a noncanonical inside-out signaling mechanism that leads to transcellular activation of a Gαq/11-coupled receptor in a neighboring (receiving) cell. This, in turn, initiates canonical outside-in signaling via PLC, leading to the hydrolysis of PIP2 and production of IP3. This process creates a regenerative, IP3-dependent signaling cascade operating between adjacent cells. Notably, neither Ca2+ nor IP3 diffusion through gap junctions plays a significant role in intercellular communication. Our findings uncover a previously unrecognized mechanism of endothelial communication, in which noncanonical IP3-driven transcellular activation of G protein-coupled receptors sustains a regenerative signaling loop, highlighting a novel framework for intercellular coordination in the vascular endothelium.

ORCID iDs

Buckley, C., Zhang, X. ORCID logoORCID: https://orcid.org/0000-0003-0790-4291, Lee, M. D. ORCID logoORCID: https://orcid.org/0000-0001-8265-382X, Wilson, C. ORCID logoORCID: https://orcid.org/0000-0003-2500-0632 and McCarron, J. G. ORCID logoORCID: https://orcid.org/0000-0002-3302-3984;
CORE (COnnecting REpositories)