Improving aortic compliance during ageing: Microtubules regulate smooth muscle cell force generation

维持血管顺应性，即血管随血压变化而改变形状的能力，对健康衰老至关重要。大动脉的血管壁即主动脉由弹性和非弹性组分组成，它们分别为血管壁提供弹性和抗拉强度。随着年龄的增长，弹性成分逐渐退化。这导致血管僵硬增加，血管顺应性降低，这是许多年龄相关疾病的危险因素。然而，防止这些弹性部件的退化是困难的。因此，沃伦实验室将重点放在血管平滑肌细胞（VSMCs）上，这是主动脉壁的主要细胞类型。这些机械敏感细胞通过产生肌动球蛋白来响应主动脉形状的变化，使血管收缩到静止状态。当主动脉壁因老化而变硬时，VSMCs的反应是产生更大的肌动球蛋白。从而防止血管壁变形，降低血管顺应性。VSMC肌动球蛋白生成力的增加与微管乙酰化的减少有关，乙酰化是微管不稳定性的标志。该项目旨在了解：(1)微管乙酰化与肌动球蛋白力产生之间的机制关系；(2)微管如何调节VSMCs通过细胞-基质粘附复合物传递肌动球蛋白的能力；(3)定向操纵微管稳定性能否调控VSMC肌动球蛋白力的产生。这项研究有可能确定新的靶点，从而允许在衰老过程中进行药理学操作和恢复主动脉顺应性。

Maintaining vascular compliance, the ability of blood vessels to change shape in response to changes in blood pressure, is essential for healthy aging. The vascular wall of large arteries, i.e. the aorta, is comprised of elastic and non-elastic components, that respectively provide elasticity and tensile strength to the vascular wall. As we age, the elastic components become degraded. This results in increased vessel stiffness and reduced vascular compliance, a risk-factor for numerous age-related diseases.However, preventing the degradation of these elastic components is difficult. The Warren Lab therefore focuses on targeting Vascular Smooth Muscle Cells (VSMCs), the principle cell type of the aortic wall. These mechanosensitive cells respond changes in aortic shape by producing actomyosin forces that contract the vessel back to its resting state. As the aortic wall stiffens due to aging, VSMCs respond by producing greater actomyosin forces. Thus, preventing the deformation of the vascular wall and reducing vascular compliance.Increased VSMC actomyosin force generation has been correlated with reduced microtubule acetylation, a marker of microtubule instability. The project seeks to understand: (1) the mechanistic relationship between microtubule acetylation and actomyosin force generation; (2) how microtubules regulate VSMCs ability to transfer actomyosin force through cell-matrix adhesion complexes; (3) whether targeted manipulation of microtubule stability can regulate VSMC actomyosin force production. This study has the potential to identify novel targets that will allow the pharmacological manipulation and restoration of aortic compliance during ageing.