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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要减缓或预防年龄引起的动脉血管舒缩功能障碍，该功能障碍与以下风险增加有关心血管疾病仍然是一个重大的临床挑战。越来越多的证据表明，单独的细胞外基质不足以完全解释血管僵硬度和动脉收缩力的丧失在衰老过程中，出现了一个新概念：血管平滑肌（VSM）细胞是重要的贡献者年龄引起的动脉功能障碍。整合素介导的信号传导对细胞骨架调节的作用老化 VSM 细胞的收缩性仍然很大程度上未知。因此，迫切需要确定年龄诱导的整合素信号改变导致血管收缩力下降的机制在老化的阻力动脉中。我们的长期目标是确定导致年龄引起的衰退的机制在动脉收缩力方面。该提案的总体目标是确定整合素信号传导至老化阻力动脉中 VSM 收缩性受损。我们的中心假设是年龄诱导的整合素功能改变会损害关键粘附蛋白的募集和应力纤维的形成导致阻力动脉的 VSM 收缩力降低。我们提出这一假设的基础是我们强有力的初步数据表明，衰老会降低关键的收缩蛋白和粘附蛋白。这些年龄—— 诱导的变化有助于 VSM 细胞向合成表型的转化，其特征是降低 VSM 细胞收缩性和阻力动脉的机械感应。拟议的理由研究表明，从机制上理解衰老如何影响整合素功能和 VSM 收缩性将有助于能够识别新的靶点来预防或逆转与年龄相关的血管收缩力丧失。这通过追求以下两个具体目标来检验假设：（1）确定整合素的贡献老化 VSM 中细胞-基质粘附的调节； (2) 确定整合素信号传导的贡献老化 VSM 中应力纤维的形成。该方法将涉及使用实时、高分辨率荧光活细胞中的原子力显微镜，以及年轻时阻力动脉的离体功能实验和老年，雄性和雌性，Fischer 344 只大鼠。拟议的研究具有创新性，因为它代表了一种新颖的整合素粘附通过控制肌动蛋白调节 ROCK/MRTF-A/SRF 激活的衰老机制应力纤维形成和肌动球蛋白激活。拟议的研究意义重大，因为了解整合素功能调节抗衰老动脉VSM收缩性的机制将填补国内空白有关年龄进展的知识。最终，这项工作对于未来关于年龄的研究至关重要通过为治疗干预提供新方向——血管重塑来诱导收缩功能丧失与降低血压相反。