Spatial uncoupling of endothelial calcium signaling from phospha-tidylserine externalization in vascular injury
- 1University of Vermont
Abstract
Ca2+ is both the signal that spreads injury information through the endothelium and the trigger for phospholipid scrambling that makes a membrane procoagulant. How a blood vessel can disseminate the first without broadcasting the second is unknown. Here, we combine single-cell laser injury in endothelial monolayers with imaging of intact mesenteric vessels in vitro and intravital Ca2+ imaging in vivo. Injury generated a coherent Ca2+ wavefront that spread rapidly before progressively slowing and terminating at a reproducible boundary 197 {+/-} 7 m from the wound, engaging 50 {+/-} 8 cells. The first ring of neighboring cells exhibited a distinct response that was prevented by carbenoxolone, whereas propagation beyond this ring required extracellular ATP, purinergic receptor activation, and IP3-dependent Ca2+ release. Wavefront kinematics were consistent with ATP diffusion. In vivo, injury elicited vasoconstriction and bidirectional Ca2+ waves propagating 205 {+/-} 28 m before terminating. Remarkably, despite widespread Ca2+ elevations, phosphatidylserine (PS) externalization remained confined to the wounded cell in monolayers and intact vessels in vitro. In contrast, ionomycin-induced Ca2+ overload exposed phosphatidylserine in nearly all endothelial cells. These findings reveal an unexpected spatial uncoupling between endothelial Ca2+ signaling and phospholipid scrambling, demonstrating that Ca2+ dependent scramblase activation is subject to additional spatial regulation. The endothelium can therefore propagate injury signals across a broad field of cells while maintaining a highly localized procoagulant membrane response.
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BibTeX
@misc{fauver2026spatial,
title = {{Spatial uncoupling of endothelial calcium signaling from phospha-tidylserine externalization in vascular injury}},
author = {O. Fauver and G. Hennig and A. Sackheim and B. Walters and R. Barba and R. Sonawane and C. Bidlack and D. Majumdar and M. Trebak and M. T. Nelson and K. Freeman},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.22.760917},
url = {https://www.biorxiv.org/content/10.64898/2026.10.22.760917v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Spatial uncoupling of endothelial calcium signaling from phospha-tidylserine externalization in vascular injury
AU - O. Fauver
AU - G. Hennig
AU - A. Sackheim
AU - B. Walters
AU - R. Barba
AU - R. Sonawane
AU - C. Bidlack
AU - D. Majumdar
AU - M. Trebak
AU - M. T. Nelson
AU - K. Freeman
PY - 2026
DA - 2026/10/22
PB - bioRxiv
DO - 10.64898/2026.10.22.760917
UR - https://www.biorxiv.org/content/10.64898/2026.10.22.760917v1
AB - Ca2+ is both the signal that spreads injury information through the endothelium and the trigger for phospholipid scrambling that makes a membrane procoagulant. How a blood vessel can disseminate the first without broadcasting the second is unknown. Here, we combine single-cell laser injury in endothelial monolayers with imaging of intact mesenteric vessels in vitro and intravital Ca2+ imaging in vivo. Injury generated a coherent Ca2+ wavefront that spread rapidly before progressively slowing and terminating at a reproducible boundary 197 {+/-} 7 m from the wound, engaging 50 {+/-} 8 cells. The first ring of neighboring cells exhibited a distinct response that was prevented by carbenoxolone, whereas propagation beyond this ring required extracellular ATP, purinergic receptor activation, and IP3-dependent Ca2+ release. Wavefront kinematics were consistent with ATP diffusion. In vivo, injury elicited vasoconstriction and bidirectional Ca2+ waves propagating 205 {+/-} 28 m before terminating. Remarkably, despite widespread Ca2+ elevations, phosphatidylserine (PS) externalization remained confined to the wounded cell in monolayers and intact vessels in vitro. In contrast, ionomycin-induced Ca2+ overload exposed phosphatidylserine in nearly all endothelial cells. These findings reveal an unexpected spatial uncoupling between endothelial Ca2+ signaling and phospholipid scrambling, demonstrating that Ca2+ dependent scramblase activation is subject to additional spatial regulation. The endothelium can therefore propagate injury signals across a broad field of cells while maintaining a highly localized procoagulant membrane response.
ER -