The role of altered cyclic strain patterns on proliferation and apoptosis of vascular smooth muscle cells - implications for in-stent restenosis
Currently, Percutaneous Transluminal Coronary Angioplasty (PTCA) followed by stent implantation is the frontline treatment in the management of coronary artery disease. To-date the main drawback of stent implantation is in-stent restenosis. Restenosis is a partial re-occlusion of the arterial wall predominantly due to vascular smooth muscle cells (SMC) migration from the media to the intima and subsequent SMC proliferation. A stent procedure dramatically alters the level of strains and stresses in the coronary artery and hence the mechanical environment of the SMC. We hypothesised that there exists a direct causal relationship between the level of strain and vascular SMC proliferation and apoptosis within the vessel wall. Cyclic strain can be seen as made by different independent components: mean strain, amplitude and frequency. In this work, the role of each strain component (mean strain, amplitude and frequency) in controlling Bovine Aortic Smooth Muscle Cells (BASMC) proliferative and apoptotic capacity was investigated. Cyclic strain decreased SMC proliferation and increased apoptosis in a temporal manner. The mean cyclic strain had no significant effect on the proliferative and apoptotic behaviour of SMC whereas SMC behaviour was highly dependent on strain amplitude. This observation was further validated using human SMC. The role of mean strain and strain amplitude was further investigated using a novel in-house phantom mock arterial system where BASMC were cultured inside a perfused stented Sylgard mock artery under physiological levels of strain. Vascular SMC proliferation was significantly increased (+40%) and apoptosis decreased within the stented region in comparison to the more compliant upstream and downstream non-stented regions of the mock Sylgard artery. We therefore conclude that the decrease in strain amplitude experienced by vascular SMC within the stented region may be responsible for SMC accumulation due to enhanced proliferation and decreased apoptosis. This study provides important evidence for the use of more compliant stent designs to maintain the anti-proliferative effect of cyclic strain on vascular SMC and therefore reduce restenosis.
Mechanical engineering, Cell biology, Biomechanics
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