Molecular mechanisms coupling matrix rigidity to DNA damage in smooth muscle

我们的血管是灵活的，这使它们能够随着血压的变化而扩张和收缩。这种灵活性对健康老龄化非常重要。主动脉是一条大的有弹性的动脉，它将血液从心脏输送出去。主动脉壁的僵硬程度决定了主动脉的柔韧性。主动脉壁含有弹性和非弹性蛋白质，两者之间的平衡决定了主动脉的灵活性。当血液流经血管时，健康的主动脉会扩张。这会导致主动脉壁伸展。拉伸会导致主动脉壁中的肌肉细胞产生力量并收缩。随着年龄的增长，我们的大动脉失去了这种灵活性。随着时间的推移，弹性的主动脉壁成分会受损，非弹性成分会累积。这种灵活性的丧失是不健康衰老的标志，并对心脏施加额外的需求，从而增加心力衰竭的风险。柔韧性下降是由于主动脉壁僵硬增加所致。我们对僵硬程度增加如何影响主动脉壁肌细胞的理解仍然很差。这项建议的中心目的是了解僵硬程度增加如何影响主动脉壁肌细胞的收缩能力。我们对这个问题的理解一直受到阻碍，因为大多数实验室都是在极其僵硬的塑料或玻璃上培养细胞。我们在一种特殊的材料上培养主动脉肌细胞，这种材料模仿健康和不健康的主动脉壁的僵硬。我们将研究不健康的主动脉壁僵硬如何影响肌肉收缩。这些研究的发现将促进我们对僵硬程度增加如何影响主动脉壁肌肉细胞的理解。这些结果将提供新的机制，为未来旨在提高血管健康的治疗提供信息。

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.