Platelets docking to VWF prevent leaks during leukocyte extravasation by stimulating Tie-2
Open Access
- 30 July 2020
- journal article
- research article
- Published by American Society of Hematology in Blood
- Vol. 136 (5), 627-639
- https://doi.org/10.1182/blood.2019003442
Abstract
Neutrophil extravasation requires opening of the endothelial barrier but does not nec-essarily cause plasma leakage. Leaks are prevented by contractile actin filaments sur-rounding the diapedesis pore, keeping this opening tightly closed around the transmigrating neutrophils. We have identified the receptor system that is responsible for this. We show that silencing, or gene inactivation, of endothelial Tie-2 results in leak formation in postcapillary venules of the inflamed cremaster muscle at sites of neutrophil extravasation, as visualized by fluorescent microspheres. Leakage was dependent on neutrophil extravasation, because it was absent upon neutrophil depletion. We identified the Cdc42 GTPase exchange factor FGD5 as a downstream target of Tie-2 that is essential for leakage prevention during neutrophil extravasation. Looking for the Tie-2 agonist and its source, we found that platelet-derived angiopoietin-1 (Angpt1) was required to prevent neutrophil-induced leaks. Intriguingly, blocking von Willebrand factor (VWF) resulted in vascular leaks during transmigration, indicating that platelets interacting with endothelial VWF activate Tie-2 by secreting Angpt1, thereby preventing diapedesis-induced leakiness.This publication has 54 references indexed in Scilit:
- Platelet ITAM signaling is critical for vascular integrity in inflammationJCI Insight, 2013
- Angiopoietin-1 Requires IQ Domain GTPase-Activating Protein 1 to Activate Rac1 and Promote Endothelial Barrier DefenseArteriosclerosis, Thrombosis, and Vascular Biology, 2011
- Dissociation of VE-PTP from VE-cadherin is required for leukocyte extravasation and for VEGF-induced vascular permeability in vivoThe Journal of Experimental Medicine, 2011
- Opening the flood-gates: how neutrophil-endothelial interactions regulate permeabilityTrends in Immunology, 2009
- Dynamics of neutrophil extravasation and vascular permeability are uncoupled during aseptic cutaneous woundingAmerican Journal of Physiology-Cell Physiology, 2009
- Leukocyte-endothelial cell interactions are linked to vascular permeability via ICAM-1-mediated signalingAmerican Journal of Physiology-Heart and Circulatory Physiology, 2008
- Platelet Granule Secretion Continuously Prevents Intratumor HemorrhageCancer Research, 2008
- Inflammation induces hemorrhage in thrombocytopeniaBlood, 2008
- Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregationJCI Insight, 2006
- ESAM supports neutrophil extravasation, activation of Rho, and VEGF-induced vascular permeabilityThe Journal of Experimental Medicine, 2006