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: 9894827
• 负责人: Hongyu Qiu
• 金额: $ 69.43万
• 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 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894827
• 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; Genes; Heart failure; Heterogeneity; Human; Hypertension; In Vitro; Individual; Kidney Failure; Link; Measurement; Mechanics; Mediating; Mediator of activation protein; Methodology; Modeling; Molecular; Muscle; Pathway Analysis; 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; experimental study; human disease; in vivo; induced pluripotent stem cell; inhibitor/antagonist; loss of function; middle age; new therapeutic target; novel; prevent; programs; reconstitution; single-cell RNA sequencing; transcription factor; 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.

项目概要 高血压是人类最常见的与年龄相关的慢性疾病之一，影响超过 1 尽管全球有数十亿人进行了数十年的深入研究，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。 血管平滑肌细胞（VSMC）僵硬度会导致主动脉僵硬度在衰老和衰老过程中增加。 我们最近的研究表明，VSMC 硬度增加与高血压密切相关。 血清反应因子 (SRF) 的上调，这是一种参与协调各种变化的主要转录因子 SRF 的药物抑制可显着降低 VSMC 硬度。 并能有效纠正成年高血压大鼠的主动脉硬化和高血压。这些发现有力地证明了这一点。 表明 SRF 是主动脉 VSMC 僵硬度的重要调节因子，也是潜在的新治疗靶点 然而，SRF 在血管老化和衰老中的生理意义。 相关的高血压尚未确定，并且根据我们的研究，其潜在机制尚未揭示。 新发现的发现，我们探索了主动脉 VSMC 中 SRF 信号的异常激活 唯一是衰老引起的主动脉硬化的关键机制；并且操纵该信号通路； 可以减缓衰老引起的主动脉硬化并预防老年人高血压的发生。 在目标 1 中，我们将通过一系列实验来检验我们的中心假设。 将确定 SRF 信号在衰老过程中主动脉硬化中的生理相关性以及对 通过使用不同的衰老和高血压大鼠模型，我们研究了老年动物高血压的发展。 将结合体内、离体和体外测量来确定 SRF 之间的相关性 主动脉僵硬度和血压（1A）的激活和病理生理学变化及其衰老 我们还将测试 SRF 的药理抑制对衰老引起的主动脉的影响。 在目标 2 中，我们将阐明 SRF 介导主动脉的机制。 我们将使用功能获得和丧失的策略来测试基因网络。 在分离的主动脉 VSMC (2A) 中受 SRF 调节，并确定年龄中 SRF 介导的细胞机制 – 诱导主动脉僵化（2B），通过结合一系列互补的生物工程技术，包括 我们将开发具有原子力显微镜和 3D 重建组织模型的新设备。 还利用人类诱导多能干细胞（iPSC）来源的 VSMC 来探索 我们在人类细胞模型中衰老引起的主动脉僵化的研究结果的转化潜力（2C）。 根据我们之前的出版物和广泛的初步研究，我们坚信我们提出的研究 将阐明年龄引起的主动脉僵化的具体机制，这将提供新的 预防和治疗与衰老相关的高血压的策略。