Molecular mechanisms coupling matrix rigidity to DNA damage in smooth muscle

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Our blood vessels are flexible and this gives them the ability to expand and contract in response to changes in blood pressure. This flexibility is important for healthy ageing. The aorta is a large elastic artery that carries blood away from the heart. The stiffness of the aortic wall determines how flexible the aorta is. The aortic wall contains elastic and non-elastic proteins and the balance between these determines the flexibility of the aortae. Healthy aorta expands as blood moves through the vessel. This results in stretching of the aortic wall. Stretching causes muscle cells in the aortic wall to generate force and contract. As we age, our aorta loses this flexibility. Over time, the elastic aortic wall components become damaged and the non-elastic components accumulate. This loss of flexibility is a hallmark of unhealthy ageing and places extra demand on the heart that increases the risk of heart failure. Decreased flexibility is driven by increased stiffness of the aortic wall. Our understanding of how increased stiffness affects the aortic wall muscle cells remains extremely poor.The central aim of this proposal is to understand how increased stiffness affects that ability of the aortic muscle cells to contract. Our understanding of this question has been hindered as most laboratories grow cells on plastic or glass, which are extremely stiff. We grow the aortic muscle cells on a special material that mimics the stiffness of the healthy and unhealthy aortic wall.We will investigate how unhealthy aortic wall stiffness affects muscle contraction. The findings from these studies will advance our understanding of how increased stiffness affects the aortic wall muscle cells. These results will provide new mechanisms that will inform on future therapies aimed at increasing vascular health.