Integrins as regulators of vascular contractility in aged resistance arteries

整合素作为老化阻力动脉血管收缩力的调节剂

• 批准号: 9809223
• 负责人: Andreea Trache
• 金额: $ 7.31万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9809223
• 关键词: Accounting; Actins; Actomyosin; Address; Adhesions; Affect; Age; Aging; Animal Model; Arteries; Atherosclerosis; Atomic Force Microscopy; Behavior; Binding; Blood Pressure; Blood Vessels; Blood flow; Cardiovascular Diseases; Cell membrane; Cell-Matrix Junction; Cells; Clinical; Cost of Illness; Data; Deposition; Development; Direct Costs; Down-Regulation; Elasticity; Elderly; Extracellular Matrix; Female; Fibroblasts; Fluorescence; Functional disorder; Future; G Actin; Genes; Goals; Grant; Hyperplasia; Hypertension; Impairment; Integrin alpha5beta1; Integrin alphaV; Integrin alphaVbeta3; Integrins; Knowledge; Link; Mechanics; Mediating; Microscopic; Mission; Molecular; Molecular Conformation; Nature; Organism; Pathway interactions; Patients; Phenotype; Phosphorylation; Play; Process; Proteins; Public Health; Rattus; Regulation; Research; Resistance; Resolution; Rho-associated kinase; Role; Serum Response Factor; Signal Transduction; Smooth Muscle Myocytes; Stimulus; Stress Fibers; Structure; Testing; Therapeutic; Therapeutic Intervention; Time; Translating; United States National Institutes of Health; Vascular Smooth Muscle; Vascular remodeling; Vasomotor; Work; age related; aged; arterial stiffness; base; blood pressure reduction; cardiovascular disorder risk; cardiovascular risk factor; disability; endothelial dysfunction; experimental study; fiber cell; human old age (65+); innovation; male; mechanical force; mechanotransduction; novel; prevent; recruit; therapy development; transcription factor; vascular contributions

PROJECT SUMMARY Slowing or preventing age-induced arterial vasomotor dysfunction that is associated with an increased risk for cardiovascular diseases remains a significant clinical challenge. Increasing evidence supports that changes in the extracellular matrix alone are insufficient to fully account for vascular stiffness and loss of arterial contractility in aging, and a new concept has emerged that vascular smooth muscle (VSM) cells are important contributors to age-induced arterial dysfunction. The role of integrin-mediated signaling to the regulation of cytoskeletal contractility in the aged VSM cells remains largely unknown. Therefore, there is a critical need to determine the mechanisms whereby age-induced alterations of integrin signaling contributes to decreased vascular contractility in aged resistance arteries. Our long-term goal is to identify mechanisms responsible for the age-induced decline in arterial contractility. The overall objective for this proposal is to determine the mechanistic contribution of integrin signaling to impaired VSM contractility in aged resistance arteries. Our central hypothesis is that age- induced alteration of integrin function impairs recruitment of key adhesion proteins and stress fiber formation resulting in reduced VSM contractility in resistance arteries. We have formulated this hypothesis on the basis of our strong preliminary data indicating that aging decreases key contractile and adhesion proteins. These age- induced changes contribute to the conversion of VSM cells to a synthetic phenotype, which is characterized by reduced VSM cell contractility and mechanosensing in resistance arteries. The rationale for the proposed research is that a mechanistic understanding of how aging affects integrin function and VSM contractility will enable the identification of novel targets to prevent or reverse age-associated loss of vascular contractility. The hypothesis will be tested by pursuing the following two specific aims: (1) Determine the contribution of integrins to the regulation of cell-matrix adhesion in aged VSM; (2) Determine the contribution of integrin signaling to stress fiber formation in aged VSM. The approach will involve the use of real-time, high-resolution fluorescence and atomic force microscopy in live cells, and ex-vivo functional experiments in resistance arteries from young and old, male and female, Fischer 344 rats. The proposed research is innovative because it represents a novel mechanism in aging by which integrin adhesion regulates ROCK/MRTF-A/SRF activation by controlling actin stress fiber formation and actomyosin activation. The proposed research is significant because understanding the mechanism by which integrin function regulates VSM contractility in aged resistance arteries will fill a gap in knowledge regarding age progression. Ultimately, this work will be critical for future studies underlying age- induced loss of contractile function by giving a new direction for therapeutic intervention - vascular remodeling as opposed to blood pressure reduction.

项目摘要 减慢或预防年龄引起的动脉血管舒缩功能障碍，这与增加的风险有关 心血管疾病仍然是一个重大的临床挑战。越来越多的证据支持改变 仅细胞外基质不足以完全解释血管僵硬和动脉收缩性的丧失 在衰老中，已经出现了一个新概念，即血管平滑肌（VSM）细胞是重要的因素 到年龄引起的动脉功能障碍。整联蛋白介导的信号传导对细胞骨架调节的作用 老年VSM细胞中的收缩力在很大程度上未知。因此，迫切需要确定 年龄引起的整联蛋白信号传导改变的机制有助于降低血管收缩力 在老化的电阻动脉中。我们的长期目标是确定导致年龄引起下降的机制 在动脉收缩性中。该提案的总体目标是确定 整联蛋白信号传导可损害老化电阻动脉中VSM收缩性。我们的中心假设是年龄 整联蛋白功能的诱导改变会破坏关键粘附蛋白和应力纤维形成的募集 导致电阻动脉的VSM收缩性降低。我们已经根据 我们强大的初步数据表明衰老会降低关键收缩和粘附蛋白。这些年龄 - 诱导的变化有助于VSM细胞转化为合成表型，其特征是 耐药性动脉中的VSM细胞收缩性和机械感应降低。提议的理由 研究是对衰老如何影响整联蛋白功能和VSM收缩力的机理理解将 允许识别新的靶标，以防止或反向与年龄相关的血管收缩损失。这 假设将通过追求以下两个具体目的来检验：（1）确定整联蛋白的贡献 调节老年VSM中细胞矩阵粘附； （2）确定整联蛋白信号传导对 年龄VSM中的应力纤维形成。该方法将涉及实时高分辨率荧光的使用 活细胞中的原子力显微镜，以及年轻的抗性动脉中的前体功能实验 和老，女性和女性，菲舍尔344只老鼠。拟议的研究具有创新性，因为它代表了一种小说 整联蛋白粘附的衰老机制通过控制肌动蛋白来调节岩石/MRTF-A/SRF激活 应力纤维形成和肌动蛋白激活。拟议的研究很重要，因为理解 整联蛋白功能调节老年电阻动脉中VSM收缩力的机制将填补空白 关于年龄发展的知识。最终，这项工作对于年龄的未来研究至关重要 - 通过给予治疗干预的新方向引起的收缩功能丧失 - 血管重塑 与降低血压相反。