Intrinsic stiffness of aortic vascular smooth muscle cell in the development of hypertension

高血压发展过程中主动脉血管平滑肌细胞的固有硬度

• 批准号: 10554120
• 负责人: Hongyu Qiu
• 金额: $ 12.33万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-12 至 2023-03-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10554120
• 关键词: 3-Dimensional; Adult; Affect; Age; Aging; American Heart Association; Animal Model; Animals; Aorta; Arteries; Atomic Force Microscopy; Biomedical Engineering; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cell Culture Techniques; Cell Differentiation process; Cells; Chronic Disease; Confocal Microscopy; Consensus; Data; Dependence; Development; Devices; Disease; Distal; Elderly; Extracellular Matrix; Gene Expression; Heart failure; Heterogeneity; Human; Hypertension; In Vitro; Individual; Kidney Failure; Link; Measurement; Mechanics; Mediating; Mediator of activation protein; Methodology; Modeling; Molecular; Muscle; Pathway Analysis; Persons; Pharmacologic Substance; Pharmacology; Physiological; Publications; Rattus; Research; Risk Factors; Role; Series; Serum Response Factor; Signal Pathway; Signal Transduction; Site; Smooth Muscle Myocytes; Specificity; Stroke; Techniques; Testing; Tissue Model; Tissues; Trees; Up-Regulation; Vascular Smooth Muscle; age related; aged; base; blood pressure elevation; experimental study; gene network; human disease; hypertensive; in vivo; induced pluripotent stem cell; inhibitor; loss of function; middle age; new therapeutic target; novel; prevent; programs; reconstitution; single-cell RNA sequencing; transcription factor; translational potential; two-photon

PROJECT SUMMARY Hypertension is one of the most common age associated chronic disorders in human and affects more than 1 billion people worldwide. Despite intense research efforts over several decades, there is still no consensus on the primary causes of this disorder and its treatment is considered mandatory. We found previously that aortic vascular smooth muscle cells (VSMCs) stiffness contributes to the increased aortic stiffness in both aging and hypertension. Our recent studies demonstrated that increased VSMC stiffness is highly associated with an upregulation of serum response factor (SRF), a master transcription factor involved in orchestrating various programs of muscle gene expression. Pharmaceutical inhibition of SRF significantly reduces VSMC stiffness and also effectively rectifies aortic stiffening and high BP in adult hypertensive rats. These findings strongly suggest that SRF is a crucial mediator of aortic VSMC stiffness and a potential novel therapeutic target for hypertensive aortic stiffness. However, the physiological significance of SRF in vascular aging and aging- related hypertension has not been established and the underlying mechanisms are unrevealed. Based on our newly findings, we hypothesized that abnormal activation of SRF signaling in VSMCs from the aorta exclusively is a key mechanism of aging-induced aortic stiffening; and that manipulating this signaling pathway can decelerate aging-induced aortic stiffening and prevent the development of hypertension in the elderly. We will test our central hypothesis by a series of experiments under the following two specific aims. In Aim 1, we will determine the physiological relevance of SRF signaling in aortic stiffening during aging and the impact on the development of hypertension in aged animals. By using different aging and hypertensive rat models, we will combine in vivo, ex vivo and in vitro measurements to determine the correlation between the SRF activation and the pathophysiological alterations in aortic stiffness and blood pressure (1A), and its aging dependency (1B). We will also test the effect of pharmacological inhibition of SRF on aging-induced aortic stiffening and hypertension (1C). In Aim 2, we will elucidate the mechanisms by which SRF mediates aortic stiffening and hypertension in aging. We will use gain- and loss-of-function strategies to test the gene network regulated by SRF in isolated aortic VSMCs (2A) and determine SRF-mediated cellular mechanisms in age– induced aortic stiffness (2B), by combining a series of complementary bioengineering techniques including new developed advancing devices with atomic force microscopy and 3D reconstituted tissue models. We will also take the advantages of human induced pluripotent stem cell (iPSC)-derived VSMCs to explore the translational potential of our findings in aging-induced aortic stiffness in human cell-based models (2C). Based on our previous publications and extensive preliminary studies, we strongly believe that our proposed studies will elucidate the specific mechanisms involved in the age-induced aortic stiffness, which will provide a new strategy for preventing and treating aging related hypertension.

项目摘要 高血压是人类中最常见的与年龄相关的慢性疾病之一，影响超过1个 全球十亿人。尽管几十年来进行了激烈的研究工作，但仍未达成共识 这种疾病及其治疗的主要原因被认为是强制性的。我们以前发现该主动脉 血管平滑肌细胞（VSMC）刚度有助于衰老和 高血压。我们最近的研究表明，VSMC刚度的增加与 血清反应因子（SRF）的上调，这是一个涉及各种策划的主转录因子 肌肉基因表达的程序。 SRF的药物抑制显着降低了VSMC刚度 并有效地纠正成年高血压大鼠的主动脉僵硬和高BP。这些发现强烈 表明SRF是主动脉VSMC刚度的关键介质，也是潜在的新型治疗靶标的 高血压主动脉僵硬。但是，SRF在血管衰老和衰老中的物理意义 - 尚未建立相关的高血压，并且基本机制未被揭示。基于我们 新发现，我们假设主动脉中VSMC中SRF信号的异常激活 完全是衰老引起的主动脉僵硬的关键机制。并操纵此信号通路 可以减速衰老诱导的主动脉僵硬并防止较早的高血压发展。我们 将通过以下两个特定目标下的一系列实验来检验我们的中心假设。在AIM 1中，我们 将确定衰老过程中主动脉僵硬中SRF信号传导的物理相关性以及对 老年动物中高血压的发展。通过使用不同的衰老和高血压大鼠模型，我们 将结合体内，离体和体外测量，以确定SRF之间的相关性 主动脉僵硬和血压（1A）的激活和病理生理改变及其衰老 依赖性（1b）。我们还将测试SRF药理抑制对衰老诱导的主动脉的影响 僵硬和高血压（1C）。在AIM 2中，我们将阐明SRF介导主动脉的机制 衰老中的僵硬和高血压。我们将使用功能丧失策略来测试基因网络 在分离的主动脉VSMC（2a）中由SRF调节，并确定年龄 - 年龄介导的细胞机制 通过组合一系列补充生物工程技术，包括 具有原子力显微镜和3D重构组织模型的新开发的前进装置。我们将 还要采用人类诱导的多能干细胞（IPSC）衍生的VSMC的优势来探索 我们发现在衰老诱导的主动脉僵硬度（2C）中的转化潜力。基于 关于以前的出版物和广泛的初步研究，我们坚信我们的拟议研究 将阐明年龄引起的主动脉僵硬涉及的特定机制，这将提供新的 预防和治疗与衰老相关的高血压的策略。