Abstract 16087: Complement Factor C5a Modulates Vein Graft Thickening and Accelerated Atherosclerosis in a Murine Model of Vein Graft Disease via Interference in Mast Cell Activation
Introduction: We previously showed that Complement activation, in particular C3 activation, is involved in vein graft disease. However, the role of other complement factors, including C5a, is unknown. Mast cells (MC), known to be present in atherosclerotic lesions, are present in the perivasculature of vein grafts and express receptors for complement factor C5a.
Hypothesis: We hypothesize that C5a acts as an activator and chemoattractant of mast cells resulting in increased vein graft disease.
Methods and Results: C5a activation of bone marrow derived MC in vitro resulted in a significant increase of tryptase release of 15% (p=0.007) as compared to non-stimulated MC, comparable with activation by C48/80, a known general MC activator. In murine vein grafts MC presence and C5a expression was studied by (immuno)histochemistry in sections of donor caval veins interpositioned in the carotid artery of recipient mice (n=3/time point). Expression of C5a and MC presence increased in time from hardly any expression at 6h to intermediate expression at 1, 3 and 7d. At the later time points of 14 and 28d after surgery, C5a was highly expressed by endothelial cells, foam cells and fibroblasts in the intimal thickening and adventitia. A significant increase in perivascular MC numbers in the vein grafts at 28d was found compared to the 6h time point of 852% (p=0.004). To asses whether C5a serves as an activator of MC in vein grafts (n=7 ApoE ko mice/group), C5a was applied locally in a pluronic gel around the vein graft during surgery or mice were treated daily with a synthetic C5a receptor antagonist. C5a application resulted in a 97% increase in number of perivascular MC and a significant increase in vein graft thickening of 65% (p=0.002) after 28d. Subsequently, the macrophage content of the vein graft was increased with 98% (p=0.006). Treatment with C5a receptor antagonist resulted in a 44% decrease in number of perivascular MC (p=0.040) and decreased vein graft thickening compared to the control group of 40% (p=0.035). The number of macrophages in the vein graft wall was decreased with 46% (p=0.012).
Conclusion: These data give a strong indication that the chemotactic potency of C5a on mast cells and the subsequent activation of these cells play an important role in vein graft disease.
- © 2010 by American Heart Association, Inc.