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.

项目总结 高血压是人类最常见的年龄相关性慢性疾病之一，影响超过1 全球有10亿人。尽管几十年来密集的研究努力，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)的僵硬是老年和老年大鼠主动脉僵直增加的原因 高血压。我们最近的研究表明，VSMC硬度的增加与 血清反应因子(SRF)是一种主要的转录因子，参与协调各种 肌肉基因表达程序。药物抑制SRF可显著降低VSMC的硬度 并能有效纠正成年高血压大鼠的主动脉僵硬和血压升高。这些发现有力地证明了 提示SRF是主动脉VSMC僵硬的重要介质，是一种潜在的新的治疗靶点。 高血压的主动脉僵硬。然而，SRF在血管衰老和衰老中的生理意义- 与高血压相关的疾病尚未得到证实，其潜在机制也未被揭示。基于我们的 新的发现，我们假设来自主动脉的VSMCs中SRF信号的异常激活 独占是衰老诱导的主动脉僵硬的一个关键机制；并且操纵这一信号通路 能减缓衰老引起的主动脉僵硬，防止老年高血压的发展。我们 我们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。在目标1中，我们 将确定SRF信号在衰老过程中主动脉硬化中的生理学相关性及其对 老年动物高血压的发生发展。通过使用不同的衰老和高血压大鼠模型，我们 将结合体内、体外和体外测量来确定SRF之间的相关性 主动脉僵硬和血压的激活和病理生理变化(1A)及其衰老 依赖性(1B)。我们还将测试SRF的药理抑制对衰老诱导的主动脉的影响 强直和高血压(1C)。在目标2中，我们将阐明srf介导主动脉的机制。 衰老时的僵硬和高血压。我们将使用获得和失去功能的策略来测试基因网络 SRF对大鼠主动脉VSMCs(2A)的调节作用及其细胞机制的研究 通过结合一系列互补的生物工程技术来诱导主动脉僵硬(2B)，包括 新开发的先进设备，具有原子力显微镜和3D重组组织模型。我们会 还利用人诱导多能干细胞(IPSC)来源的VSMCs的优势来探索 我们在人类细胞模型中发现的衰老诱导的主动脉僵硬的翻译潜力(2C)。基座 根据我们之前的出版物和广泛的初步研究，我们坚信我们提议的研究 将为阐明增龄性主动脉僵硬的具体机制提供新的研究方向。 老年高血压的防治策略。