title: Mechanism and functional impact of CD40 ligand-induced von Willebrand factor release from endothelial cells.
abstract: Co-stimulation via CD154 binding to CD40, pivotal for both innate and adaptive immunity, may also link haemostasis to vascular remodelling. Here we demonstrate that human platelet-bound or recombinant soluble CD154 (sCD154) elicit the release from and tethering of ultra-large (UL) von Willebrand factor (vWF) multimers to the surface of human cultured endothelial cells (ECs) exposed to shear stress. This CD40-mediated ULVWF multimer release from the Weibel-Palade bodies was triggered by consecutive activation of TRAF6, the tyrosine kinase c-Src and phospholipase Cγ1 followed by inositol-1,4,5 trisphosphate-mediated calcium mobilisation. Subsequent exposure to human washed platelets caused ULVWF multimer-platelet string formation on the EC surface in a shear stress-dependent manner. Platelets tethered to these ULVWF multimers exhibited P-selectin on their surface and captured labelled monocytes from the superfusate. When exposed to shear stress and sCD154, native ECs from wild-type but not CD40 or vWF-deficient mice revealed a comparable release of ULVWF multimers to which murine washed platelets rapidly adhered, turning P-selectin-positive and subsequently capturing monocytes from the perfusate. This novel CD154-provoked ULVWF multimer-platelet string formation at normal to fast flow may contribute to vascular remodelling processes requiring the perivascular or intravascular accumulation of pro-inflammatory macrophages such as arteriogenesis or atherosclerosis.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Möller
authors.forename: Oliver
authors.initials: O
authors.lastname: Adolph
authors.forename: Jennifer
authors.initials: J
authors.lastname: Grünow
authors.forename: Julia
authors.initials: J
authors.lastname: Elrod
authors.forename: Miruna
authors.initials: M
authors.lastname: Popa
authors.forename: Subhajit
authors.initials: S
authors.lastname: Ghosh
authors.forename: Manuel
authors.initials: M
authors.lastname: Schwarz
authors.forename: Chrysovalandis
authors.initials: C
authors.lastname: Schwale
authors.forename: Sandra
authors.initials: S
authors.lastname: Grässle
authors.forename: Volker
authors.initials: V
authors.lastname: Huck
authors.forename: Claus
authors.initials: C
authors.lastname: Bruehl
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Schneider
authors.forename: Rainer
authors.initials: R
authors.lastname: Nobiling
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Wagner
authors.affiliation: Markus Hecker, PhD DSc, Institute of Physiology and Pathophysiology, Division of Cardiovascular Physiology, Heidelberg University, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany, Tel.: +49 6221 54 4035, Fax +49 6221 54 4038, E-mail: hecker@physiologie.uni-heidelberg.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Hecker
mesh_terms: D000818:Animals; D001158:Arteries / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism*; D002118:Calcium / Q000737:chemistry; D017536:Carotid Artery, Common / Q000473:pathology; D002448:Cell Adhesion; D004594:Electrophysiology; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation; D007511:Ischemia / Q000473:pathology; D051379:Mice; D008856:Microscopy, Fluorescence; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D010477:Perfusion; D011994:Recombinant Proteins / Q000378:metabolism; D033081:Shear Strength; D015398:Signal Transduction; D020521:Stroke; D010738:Type C Phospholipases / Q000378:metabolism; D020302:Weibel-Palade Bodies / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D019007:P-Selectin; D011994:Recombinant Proteins; C546937:SELP protein, human; D014841:von Willebrand Factor; D023201:CD40 Ligand; D010738:Type C Phospholipases; D002118:Calcium
keywords: CD154; CD40; endothelial cells; monocyte/macrophages; platelets; remodelling; vascular; von Willebrand factor