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

改善衰老过程中的主动脉顺应性：微管调节平滑肌细胞力的产生

• 批准号: 2585702
• 金额: --
• 依托单位: University of East Anglia
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2585702
• 关键词: Improving; aortic; compliance; during; ageing

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.

保持血管顺应性，即血管对血压变化的反应形状的能力，对健康衰老至关重要。大动脉的血管壁，即主动脉，由弹性和非弹性成分组成，它们分别为血管壁提供弹性和拉伸强度。随着年龄的增长，弹性成分会退化。这会导致血管僵硬增加和血管顺应性降低，这是许多与年龄相关的疾病的危险因素。然而，防止这些弹性成分的降解是困难的。因此，沃伦实验室专注于针对血管平滑肌细胞(VSMCs)，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球蛋白力来响应主动脉形状的变化，从而将血管收缩回其静止状态。随着年龄的增长，主动脉壁变硬，VSMC通过产生更大的肌动球蛋白力量来做出反应。因此，防止血管壁的变形和降低血管的顺应性。VSMC肌动球蛋白产生的增加与微管乙酰化的减少相关，微管乙酰化是微管不稳定的标志。该项目试图了解：(1)微管乙酰化和肌动球蛋白力产生之间的机制关系；(2)微管如何通过细胞-基质黏附复合体调节VSMC转移肌球蛋白力的能力；(3)靶向操纵微管稳定性是否可以调节VSMC肌动球蛋白力的产生。这项研究具有确定新靶点的潜力，这些靶点将允许在衰老期间进行药物操作和恢复主动脉顺应性。