Studies on the role of the endocannabinoid anandamide, as a possible modulator of events during neointimal formation.
Skene, Karen E.
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Neointimal formation is a complex process that occurs due to the over compensatory healing response produced by the vessel following injury. Three key events, SMC proliferation, SMC migration and the inflammatory response, occur in unison to drive the formation of a neointima. Cannabinoids/endocannabinoids have been shown to elicit antiproliferative, anti-migratory and anti-inflammatory effects, highlighting modulation of the endocannabinoid system as possible therapeutic strategy. The aims of this study were to; (i) develop an organ culture model of neointimal formation, and investigate the presence of the endocannabinoid system, (ii) investigate the functional response of anandamide (AEA) in the murine carotid artery, (iii) investigate the effects of cannabinoids on SMC proliferation, and (iv) to establish the effects of cannabinoids on SMC migration. The organ culture model developed in this study demonstrated the presence of both CB receptors on SMCs, LCMS/MS analysis of tissue samples showed that endocannabinoid concentration was significantly (2-arachidonoylglycerol / 2-AG) increased in injured artery sections. Isolated vessel studies demonstrated that AEA produces a small (~20%) relaxation of the murine carotid artery which was not dependant on the production of active metabolites, but involved activation of the CB1 receptor. Studies investigating the effects of cannabinoids on cell proliferation revealed that paradoxically both a CB2 agonist and a CB2 antagonist reduced markers of cell proliferation without any effect on cell viability; high concentrations of AEA (10μM) reduced SMC proliferation, however this was associated with an apparent cytotoxic/cytostatic effect. The preliminary data from cell migration studies suggests that a CB2 agonist may function to reduce stimulated cell migration and that 2-AG can increase migration of unstimulated SMCs. In conclusion, although further research is required, the data within this thesis provides evidence that the endocannabinoid system (in particular the CB2 receptor) may have the potential to be manipulated for therapeutic gains in terms of restenosis.