Implication of adenylyl cyclase 8 in pathological smooth muscle cell migration occurring in rat and human vascular remodelling.
Recently, we discovered on primary cell cultures that adenylyl cyclase type 8 (AC8) was involved in the transition of rat vascular smooth muscle cells (VSMCs) to an inflammatory phenotype. Here we demonstrate, in human vessels displaying early or advanced atherosclerotic lesions, that: (a) only intimal VSMCs strongly express AC8; and (b) very few AC8-positive VSMCs were detected in the medial layer, either in atherosclerotic or healthy arteries. Furthermore, over-expressing AC8 in primary rat VSMC cultures triggered the recolonization of a wounded zone and similar results were obtained in the presence of mitomycin, a potent inhibitor of proliferation. This phenomenon was prevented by silencing AC8. Indeed, in IL-1 beta-treated cells, AC8 silencing halted migration and decreased the matrix-metalloproteinases 2/9 secretion, known to be involved in VSMC migration. In vivo, we showed: (a) a pronounced up-regulation of AC8 expression in highly migrating VSMCs of the injured rat carotid artery; (b) an undetectable AC8 labelling in re-endothelized vessels where neo-intimal thickening had stopped. From our data, we conclude that AC8 expression appears closely linked to the properties developed by VSMCs in atherosclerosis and post-angioplasty neo-intima formation leading to restenosis. In addition, it reinforces the idea that VSMC responses to their cell environment greatly depend on the AC isoforms expressed and attributes a new role for AC8 in these pathological vascular processes.
Univ Paris 06, UR4, Paris, France.
Marie
M
Gueguen
Zela
Z
Keuylian
Véronique
V
Mateo
Nathalie
N
Mougenot
Anne-Marie
AM
Lompré
Jean-Baptiste
JB
Michel
Olivier
O
Meilhac
Larissa
L
Lipskaia
Isabelle
I
Limon
D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology* / Q000473:pathology; D020212:Carotid Artery Injuries / Q000201:enzymology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D053583:Interleukin-1beta; D034741:RNA, Small Interfering; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000262:Adenylyl Cyclases; C118292:adenylyl cyclase 8