The neuropeptide substance P mediates adventitial mast cell activation and induces intraplaque hemorrhage in advanced atherosclerosis.

Abstract

Although we and others have recently shown that mast cells play an important role in plaque progression and destabilization, the nature of the actual trigger for (peri)vascular mast cell activation during atherosclerosis is still unresolved. In this study, we confirm that perivascular mast cell content correlates with the number of nerve fibers in the adventitia of human coronary atherosclerotic plaque specimen. Because peripheral C-type nerve fibers secrete, among others, substance P, a potent mast cell activator, we set out to study effects of adventitial administration of this neuropeptide on mast cell dependent destabilization of carotid artery plaques in apolipoprotein E-deficient (apoE(-/-)) mice. Substance P treatment significantly enhanced the number and activation status of adventitial mast cells compared to controls and promoted intraplaque hemorrhages. These phenomena could be prevented by coadministration of the neurokinin-1 receptor antagonist spantide I and did not occur in mast cell deficient apoE(-/-) mice, establishing the critical involvement of mast cells in substance P-elicited plaque destabilization. Our data suggest that neurotransmitters such as substance P are capable of promoting mast cell dependent plaque destabilization and provide a new, direct link between neural factors and vascular inflammation.