title: Endogenous cannabinoid receptor CB1 activation promotes vascular smooth-muscle cell proliferation and neointima formation.
abstract: Percutaneous transluminal angioplasty is frequently used in patients with severe arterial narrowing due to atherosclerosis. However, it induces severe arterial injury and an inflammatory response leading to restenosis. Here, we studied a potential activation of the endocannabinoid system and the effect of FA amide hydrolase (FAAH) deficiency, the major enzyme responsible for endocannabinoid anandamide degradation, in arterial injury. We performed carotid balloon injury in atherosclerosis-prone apoE knockout (apoE(-/-)) and apoE(-/-)FAAH(-/-) mice. Anandamide levels were systemically elevated in apoE(-/-) mice after balloon injury. ApoE(-/-)FAAH(-/-) mice had significantly higher baseline anandamide levels and enhanced neointima formation compared with apoE(-/-) controls. The latter effect was inhibited by treatment with CB1 antagonist AM281. Similarly, apoE(-/-) mice treated with AM281 had reduced neointimal areas, reduced lesional vascular smooth-muscle cell (SMC) content, and proliferating cell counts. The lesional macrophage content was unchanged. In vitro proliferation rates were significantly reduced in CB1(-/-) SMCs or when treating apoE(-/-) or apoE(-/-)FAAH(-/-) SMCs with AM281. Macrophage in vitro adhesion and migration were marginally affected by CB1 deficiency. Reendothelialization was not inhibited by treatment with AM281. In conclusion, endogenous CB1 activation contributes to vascular SMC proliferation and neointima formation in response to arterial injury.
authors.affiliation: Division of Cardiology, University Hospital, Geneva, Switzerland.
authors.forename: Filippo
authors.initials: F
authors.lastname: Molica
authors.forename: Fabienne
authors.initials: F
authors.lastname: Burger
authors.forename: Aurélien
authors.initials: A
authors.lastname: Thomas
authors.forename: Christian
authors.initials: C
authors.lastname: Staub
authors.forename: Anne
authors.initials: A
authors.lastname: Tailleux
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Graziano
authors.initials: G
authors.lastname: Pelli
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.forename: Benjamin
authors.initials: B
authors.lastname: Cravatt
authors.forename: Christian M
authors.initials: CM
authors.lastname: Matter
authors.forename: Pal
authors.initials: P
authors.lastname: Pacher
authors.forename: Sabine
authors.initials: S
authors.lastname: Steffens
mesh_terms: D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D058426:Neointima / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017539:Tunica Intima / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001057:Apolipoproteins E; D009025:Morpholines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C109925:AM 281