title: The neuropeptide substance P mediates adventitial mast cell activation and induces intraplaque hemorrhage in advanced atherosclerosis.
abstract: 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.
authors.affiliation: 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
authors.forename: Ilze
authors.initials: I
authors.lastname: Bot
authors.forename: Saskia C A
authors.initials: SC
authors.lastname: de Jager
authors.forename: Martine
authors.initials: M
authors.lastname: Bot
authors.forename: Sandra H
authors.initials: SH
authors.lastname: van Heiningen
authors.forename: Paul
authors.initials: P
authors.lastname: de Groot
authors.forename: Roel W
authors.initials: RW
authors.lastname: Veldhuizen
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: van Berkel
authors.forename: Jan H
authors.initials: JH
authors.lastname: von der Thüsen
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
mesh_terms: 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
chemical_list: D000700:Analgesics; D001057:Apolipoproteins E; D064729:Neurokinin-1 Receptor Antagonists; D018377:Neurotransmitter Agents; D018040:Receptors, Neurokinin-1; D013373:Substance P; C042867:spantide