Platelets docking to VWF prevent leaks during leukocyte extravasation by stimulating Tie-2

• Published in: Blood Vol. 136; no. 5; pp. 627 - 639
• Main Authors: Braun, Laura J., Stegmeyer, Rebekka I., Schäfer, Kerstin, Volkery, Stefan, Currie, Silke M., Kempe, Birgit, Nottebaum, Astrid F., Vestweber, Dietmar
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30-07-2020; American Society of Hematology
• Subjects: Angiopoietin-1 - metabolism; Animals; Blood Platelets; Capillary Permeability - physiology; Human Umbilical Vein Endothelial Cells; Humans; Leukocytes; Mice; Mice, Inbred C57BL; Receptor, TIE-2 - metabolism; Transendothelial and Transepithelial Migration - physiology; Vascular Biology; von Willebrand Factor - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2019003442

Neutrophil extravasation requires opening of the endothelial barrier but does not necessarily cause plasma leakage. Leaks are prevented by contractile actin filaments surrounding 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.
•Platelets prevent plasma leakage during neutrophil diapedesis by binding to endothelial VWF and releasing Angpt1.•Platelet-released Angpt1 stimulates endothelial Tie-2, thereby activating the GEF FGD5, which strengthens cortical actin bundles.
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