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

: Neutrophil extravasation requires opening of the endothelial barrier, but does not automatically cause plasma leakage. Leaks are prevented by contractile actin filaments surrounding the diapedesis-pore keeping this opening tightly closed around the transmigrating neutrophils. Here, we have identified the receptor system which is responsible for this. We show that silencing, or gene inactivation of endothelial Tie-2 each result in leak formation in postcapillary venules of the inflamed cremaster at sites of neutrophil extravasation as visualized by fluorescent microspheres. Leakage was dependent on neutrophil extravasation, since it was absent upon neutrophil depletion. As downstream target of Tie-2 we identified the Cdc42 GTPase exchange factor FGD5 as essential for leakage prevention during neutrophil extravasation. Seeking for the Tie-2 agonist and its source we found that platelet derived Angiopoietin-1 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 Angiopoietin-1, thereby preventing diapedesis-induced leakiness.