Cardiovascular diseases are a major cause of death worldwide. Aneurysmal rupture in cerebral arteries or loss of endothelial integrity in the course of atherosclerosis or therapeutic angioplasty lead to exposure of vascular smooth muscle cells (SMC) to blood components such as sphingolipids. Sphingosylphosphorylcholine (SPC) and sphingosine 1-phosphate (S1P) are two naturally occurring sphingolipids, which are vasoprotective in the healthy endothelium-lined vessel, but may promote vascular disease by causing functional changes of SMC. Vascular inflammation is an important factor in various pathologies. SPC can activate pro-inflammatory signalling pathways in rat cerebral artery. Here these observations are extended by showing that SPC elicits monocyte chemoattractant protein-1 production in rat cerebral artery SMC ex vivo. Thus, in addition to being a vasoconstrictor, SPC may promote the development of life-threatening prolonged cerebral vasospasm following subarachnoid haemorrhage by supporting vascular inflammation. It is also demonstrated that SPC prevents tumour necrosis factor-a (TNF)-stimulated adhesion of macrophages to rat aortic SMC in vitro by interfering with adhesive properties of SMC, but not macrophages. While this effect appeared to be mediated by the S1P receptor S1P2, S1P itself did not reduce macrophage adhesion. The anti-adhesive action of SPC also depended on lipid rafts. However, SPC did neither prevent TNF-induced nuclear factor kB activation nor cell adhesion molecule expression in SMC. SPC-induced cyclooxygenase 2 expression in aortic SMC was dispensable for its anti-adhesive effect. In contrast, the inhibitory effect of SPC on TNFinduced expression of inducible nitric oxide synthase is probably involved in its anti-adhesive effect because it was mimicked by respective pharmacological blockade. The results also demonstrate that nitric oxide promotes leukocyte adhesion to vascular SMC, while it has the opposite effect on endothelial cells. These findings may help understand cardiovascular diseases and define novel treatment approaches.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:558636 |
| Date | January 2012 |
| Creators | Wirrig, Christiane |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=185829 |
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