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


OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
Bot
Ilze
I
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands. i.bot@lacdr.leidenuniv.nl
de Jager
Saskia C A
SC
Bot
Martine
M
van Heiningen
Sandra H
SH
de Groot
Paul
P
Veldhuizen
Roel W
RW
van Berkel
Theo J C
TJ
von der Thüsen
Jan H
JH
Biessen
Erik A L
EA
D000368:Aged; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D003238:Connective Tissue / Q000378:metabolism* / Q000473:pathology; D003324:Coronary Artery Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006470:Hemorrhage / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D064729:Neurokinin-1 Receptor Antagonists; D018377:Neurotransmitter Agents / Q000378:metabolism* / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000378:metabolism; D013373:Substance P / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D014657:Vasculitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D000700:Analgesics; D001057:Apolipoproteins E; D064729:Neurokinin-1 Receptor Antagonists; D018377:Neurotransmitter Agents; D018040:Receptors, Neurokinin-1; D013373:Substance P; C042867:spantide