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 高血压是人类最常见的与年龄相关的慢性疾病之一， 全球十亿人。尽管几十年来进行了大量的研究，但仍然没有达成共识。 这种疾病的主要原因及其治疗被认为是强制性的。我们之前发现主动脉 血管平滑肌细胞（VSMCs）的僵硬度有助于增加主动脉僵硬度， 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，SRF是一种参与协调各种 肌肉基因表达的程序。药物抑制SRF显著降低VSMC刚度 并有效纠正成年高血压大鼠的主动脉硬化和高血压。这些发现强烈 表明SRF是主动脉VSMC僵硬重要介质，是一个潜在的新的治疗靶点， 高血压性主动脉僵硬然而，SRF在血管老化和衰老中的生理意义- 相关的高血压尚未建立，其潜在机制尚未揭示。基于我们 新的发现，我们假设SRF信号在主动脉VSMCs的异常激活， 是衰老诱导的主动脉硬化的关键机制;操纵这一信号通路 可减缓衰老引起的主动脉硬化，预防老年人高血压的发展。我们 我将在以下两个具体目标下通过一系列实验来检验我们的中心假设。目标1： 将确定SRF信号在老化过程中主动脉硬化中的生理相关性，以及对 老年动物高血压的发展。通过使用不同的衰老和高血压大鼠模型， 将结合联合收割机体内、离体和体外测量来确定SRF之间的相关性 激活和主动脉僵硬度和血压的病理生理学改变（1A），以及其老化 依赖关系（1B）。我们还将测试SRF的药理学抑制对衰老诱导的主动脉的作用。 硬化和高血压（1C）。在目的2中，我们将阐明SRF介导主动脉粥样硬化的机制， 变硬和高血压。我们将使用功能获得和功能丧失策略来测试基因网络 在分离的主动脉VSMC中由SRF调节（2A），并确定SRF介导的细胞机制在年龄- 通过结合一系列互补的生物工程技术，包括 新开发的先进设备与原子力显微镜和3D重建组织模型。我们将 利用人诱导性多能干细胞（iPSC）来源的VSMCs的优势， 我们的发现在基于人类细胞的模型中的老化诱导的主动脉僵硬中的转化潜力（2C）。基于 根据我们以前的出版物和广泛的初步研究，我们坚信我们提出的研究 将阐明年龄引起的主动脉僵硬的具体机制，这将提供一个新的 老年性高血压的防治策略