Abstract 5066: Substance P Mediated Adventitial Mast Cell Activation Induces Intraplaque Hemorrhage in Advanced Atherosclerosis
Previously, we and others have shown that mast cells, present in intima and adventitia of advanced atherosclerotic lesions, play an important role in plaque progression and destabilization. However, the nature of the endogenous trigger for activation of these (peri)vascular cells during atherosclerosis is still unresolved. In this study, we show that perivascular mast cell content as demonstrated by CD117 staining correlates with the number of neurofilament+ nerve fibers in the adventitia of human coronary atherosclerotic plaque specimens (P<0.05, r=0.42), suggestive of neural regulation of mast cell activation. Our attention turned to the neuropeptide substance P (SP) as mediator of mast cell activation via the neurokinin-1 receptor. Local perivascular administration of SP (0.1 nmol in 25% (w/v) F-127 pluronic gel) to advanced carotid artery plaques in apoE−/− mice did not affect plaque size at 3 days after challenge (SP: 67±14*103 μm2 versus controls: 51±10*103 μm2, P=NS), however the number of adventitial mast cells was significantly enhanced in SP treated mice compared to PBS controls (4.9±0.8 versus 2.2±0.5 mast cells/mm2 adventitial tissue, P<0.01). Also, mast cell activation status was increased in the SP challenged group (56±9% compared to 29±9% in controls, P<0.05). This was accompanied by a significant increase in the incidence of intraplaque hemorrhages (IPHs) in SP treated mice (5/12 compared to 0/15 in controls, P=0.01). SP mediated mast cell recruitment was inhibited by co-administration of the neurokinin-1 receptor antagonist Spantide-I (2.6±0.4 mast cells/mm2 adventitial tissue, P<0.01), while in these mice hardly any IPHs occurred (1/16, P=0.06). Furthermore, SP was not effective in inducing IPHs in advanced carotid artery plaques of mast cell deficient apoE−/−Kit(W−sh/W−sh) mice (1/18, P<0.05), establishing the critical involvement of mast cells in SP elicited plaque destabilization. In conclusion, our data suggest that neurotransmitters such as SP are capable of promoting mast cell dependent plaque destabilization and our study thus provides a new, direct link between neural factors and vascular inflammation involving mast cells, which may be particularly relevant in acute cardiovascular syndromes.