Abstract
Aims: Mast cells are versatile innate immune cells and are reported to promote vascular inflammation and neointimal lesion formation, thereby contributing to the development of vascular stenosis and atherosclerosis. However, it is not clear whether mast cells also regulate vascular matrix remodelling in established neointima. This study addressed the hypothesis that perivascular mast cells regulate neointimal matrix remodelling using a mouse vein graft model. Methods: The impact of mast cells on neointimal remodelling was investigated using mast cell-deficient animals in both normolipidaemic (KitW-sh/W-sh) and hyperlipidaemic (apoE-/-KitW-sh/W-sh) conditions. The effect of perivascular mast cells on vascular matrix remodelling, including collagen and elastin deposition, was investigated using a local mast cell reconstitution method that selectively repopulated mast cells around the carotid artery (where the vein graft was inserted) in KitW-sh/W-sh mice. Results: In normolipidaemic vein grafts (KitW-sh/W-sh vs. the wild type control C57BL/6J), collagen synthesis was not affected by mast cell deficiency at 4 weeks. In contrast, neointimal elastin was reduced by 6.5-fold in mast cell-deficient KitW-sh/W-sh mice, which was prevented by perivascular mast cell reconstitution. Mast cell deficiency induced a similar reduction in neointimal elastin in hyperlipidaemic mice (apoE-/-KitW-sh/W-sh vs. apoE-/-), with a significant increase in cell proliferation and neointimal area at 4 week. Conclusion: Mast cells appear to promote elastin deposition in vein grafts and this may lead to further suppression of cell proliferation and neointimal thickening under hyperlipidaemic conditions.
Highlights
Mast cells are versatile innate immune cells, wellknown for their role in inflammation and innate immunity.[1,2] Despite the wide distribution of mast cells in arterial adventitia and perivascular connective tissue, our understanding of the influence of mast cells in vascular disease is limited
This study demonstrates firstly that perivascular mast cells elevate neointimal elastin deposition under both normolipidaemic and hyperlipidaemic conditions, and secondly that they suppress neointimal thickening in hyperlipidaemic mice possibly via down regulation of cell proliferation within the vein graft
The present study demonstrates that mast cells play a previously unrecognised role in promotion of elastin deposition during vein graft remodelling
Summary
Mast cells are versatile innate immune cells, wellknown for their role in inflammation and innate immunity.[1,2] Despite the wide distribution of mast cells in arterial adventitia and perivascular connective tissue, our understanding of the influence of mast cells in vascular disease is limited. In recent years, accumulating evidence suggests that mast cells promote vascular inflammation and contribute to the progression of a number of vascular diseases including atherosclerosis, aortic aneurysm and vein graft neointima hyperplasia.[3,4,5,6] Systemic activation of mast cells using dinitrophenyl-albumin increased plaque size in apoE-/- mice, whilst selective stimulation of perivascular mast cells had no impact on plaque formation but destabilised established plaque with increased intraplaque haemorrhage.[7] Compound 48/80, another mast cell activator, demonstrated a similar effect to promote atherosclerosis development, which was inhibited by the mast cell stabiliser cromolyn.[8,9] In addition to pharmacological manipulation of mast cell function, studies using genetic mast cell deficiency (as a consequence of spontaneous mutation in the promoter region of the c-kit gene[10]) confirmed the detrimental effect of mast cells in atherosclerosis.[3] Mechanistic studies revealed that activated mast cells synthesised and released a wide range of proinflammatory factors including interleukin (IL)-6 and IL-8, interferon gamma, tumournecrosis factor alpha, histamine, chymase and tryptase. Mast cells exacerbated vascular inflammation with increased intra-plaque leukocyte infiltration, lipid uptake, vascular matrix degradation and subsequent plaque expansion and destabilisation.[6]
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