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

Kerstin Möller; Oliver Adolph; Jennifer Grünow; Julia Elrod; Miruna Popa; Subhajit Ghosh; Manuel Schwarz; Chrysovalandis Schwale; Sandra Grässle; Volker Huck; Claus Bruehl; Thomas Wieland; Stefan W. Schneider; Rainer Nobiling; Andreas H. Wagner; Markus Hecker

doi:10.1160/TH14-04-0336

Thrombosis and Haemostasis, Inhaltsverzeichnis

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^†

¹Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany

,

Oliver Adolph^†

¹Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany

,

Jennifer Grünow

¹Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany

,

Julia Elrod

¹Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany

,

Miruna Popa

¹Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany

,

Subhajit Ghosh

¹Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany

,

Manuel Schwarz

¹Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany

,

Chrysovalandis Schwale

²Division of Neuro- and Sensory Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany

,

Sandra Grässle

³Division of Experimental Dermatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

,

Volker Huck

³Division of Experimental Dermatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

,

Claus Bruehl

²Division of Neuro- and Sensory Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany

,

Thomas Wieland

⁴Institute for Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

,

Stefan W. Schneider

³Division of Experimental Dermatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

,

Rainer Nobiling

¹Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany

,

Andreas H. Wagner^‡

¹Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany

,

Markus Hecker^‡

¹Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany

› Institutsangaben

Abstract

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

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Referenzen

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