Abstract
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. We sought to determine the role of mast cells (MCs) in DVT initiation and validate MCs as a potential target for DVT prevention. In a mouse model, DVT was induced by partial ligation (stenosis) of the inferior vena cava. We demonstrated that 2 strains of mice deficient for MCs were completely protected from DVT. Adoptive transfer of in vitro differentiated MCs restored thrombosis. MCs 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 inferior vena cava 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. MC releasate elevated ICAM-1 (intercellular adhesion molecule-1) expression on HUVEC (human umbilical vein endothelial cells) 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. MCs exacerbate DVT likely through endothelial activation and Weibel-Palade body release, which is, at least in part, mediated by histamine. Because MCs do not directly contribute to normal hemostasis, they can be considered potential targets for prevention of DVT in humans.
Highlights
Rationale: Deep vein thrombosis (DVT) and its complication pulmonary embolism have high morbidity reducing quality of life and leading to death
We demonstrated that 2 strains of mice deficient for Mast cells (MCs) were completely protected from DVT
MCs were present in the venous wall, and the number of granule-containing MCs decreased with thrombosis
Summary
AnimalsMC-deficient KitW-v (Jackson Laboratory 000049, backcrossed to C57BL/6J for decades) mice[25] and KitW-sh (Jackson Laboratory 012861, backcrossed to C57BL/6J for 11 generations) mice[26,27] were purchased in the Jackson Laboratory, and colonies were maintained in animal facilities at Children’s Hospital Boston and the University of Birmingham under standard conditions. The IVC was gently isolated from aorta, a 7-0 polypropylene suture was placed over the IVC, and ligated over a spacer (30-gauge needle), and the spacer was removed. This method produces IVC lumen area reduction by ≈90% and is not accompanied by endothelial denudation. In 8 – 10 weeks, mice were subjected to 48 h IVC stenosis. Frozen sections were submerged in absolute ethanol, washed with running water and subjected to staining in Toluidine blue (TB) solution for 1 min. After staining sections were washed with running water, submerged in 95% and 100% ethanol, soaked in a clearant and mounted with hydrophobic mount.
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