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Thromb Haemost 2015; 113(05): 1095-1108
DOI: 10.1160/TH14-04-0336
Cellular Signalling and Proteolysis
Schattauer GmbH

Mechanism and functional impact of CD40 ligand-induced von Willebrand factor release from endothelial cells

Kerstin Möller   †
1   Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
,
Oliver Adolph   †
1   Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
,
Jennifer Grünow
1   Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
,
Julia Elrod
1   Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
,
Miruna Popa
1   Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
,
Subhajit Ghosh
1   Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
,
Manuel Schwarz
1   Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
,
Chrysovalandis Schwale
2   Division of Neuro- and Sensory Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
,
Sandra Grässle
3   Division of Experimental Dermatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
,
Volker Huck
3   Division of Experimental Dermatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
,
Claus Bruehl
2   Division of Neuro- and Sensory Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
,
Thomas Wieland
4   Institute for Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
,
Stefan W. Schneider
3   Division of Experimental Dermatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
,
Rainer Nobiling
1   Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
,
Andreas H. Wagner   ‡
1   Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
,
Markus Hecker   ‡
1   Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
› Author Affiliations Financial support: This work was supported by a grant from the Deutsche Forschungsgemeinschaft (TRR 23 project sections MGK, A9, B6 and C6, and FOR 1543 project section A2), the European Commission (Marie-Curie ITN SmArt and SmArteR), and internal funds.
Further Information

Publication History

Received: 11 April 2014

Accepted after major revision: 28 January 2014

Publication Date:
24 November 2017 (online)

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Summary

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 tris-phosphate-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 multimerplatelet 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.

Keywords

CD40 - CD154 - endothelial cells - von Willebrand factor - platelets - monocyte/macrophages - remodelling - vascular

† K.M and O. A. contributed equally to this work.


‡ A. H. W. and M. H. contributed equally to this work.


 

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