Mast cells granular contents are crucial for deep vein thrombosis in mice

Research output: Contribution to journalArticlepeer-review

Authors

Abstract

Rationale: Deep vein thrombosis (DVT) and its complication pulmonary embolism have high morbidity reducing quality of life and leading to death. Cellular mechanisms of DVT initiation remain poorly understood.
Objective: We sought to determine the role of mast cells (MCs) in DVT initiation and validate MCs as a potential target for DVT prevention.
Methods and Results: In a mouse model, DVT was induced by partial ligation (stenosis) of the inferior vena cava (IVC). We demonstrated that two strains of mice deficient for MCs were completely protected from DVT. Adoptive transfer of in vitro differentiated MCs restored thrombosis. Mast cells were present in the venous wall, and the number of granule-containing MCs decreased with thrombosis. Pharmacological depletion of MCs granules or prevention of MC degranulation also reduced DVT. Basal plasma levels of von Willebrand factor and recruitment of platelets to the IVC wall after DVT induction were reduced in MC-deficient mice. Stenosis application increased plasma levels of soluble P-selectin in wild-type but not in MC-deficient mice. Mast cell releasate elevated ICAM-1 expression on HUVEC in vitro. Topical application of compound 48-80, an MC secretagogue, or histamine, a Weibel-Palade body secretagogue from MCs, potentiated DVT in wild-type mice, and histamine restored thrombosis in MC-deficient animals.
Conclusions: Mast cells exacerbate DVT likely through endothelial activation and Weibel-Palade body release, which is, at least in part, mediated by histamine. As MCs do not directly contribute to normal hemostasis, they can be considered potential targets for prevention of DVT in humans.

Details

Original languageEnglish
Pages (from-to)941-950
JournalCirculation Research
Volume121
Issue number8
Early online date24 Jul 2017
Publication statusPublished - 29 Sep 2017

Keywords

  • deep vein thrombosis, thrombosis, histamine, endothelial cell, animal model cardiovascular disease, mast cells