The Effect of Perivascular Adipose Tissue Inflammation and Sympathetic Activity on Arterial Stiffening

血管周围脂肪组织炎症和交感神经活动对动脉硬化的影响

• 批准号: 1916814
• 负责人: Alisa Clyne
• 金额: $ 48.13万
• 依托单位: Drexel University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1916814&HistoricalAwards=false
• 关键词: Effect; Perivascular; Adipose; Tissue; Inflammation

Stiffening of arteries is a significant contributor to vascular disease, which leads to high blood pressure, cardiovascular disease, stroke and other significant medical conditions. Arterial stiffness is largely determined by the function of vascular smooth muscle cells. When vascular smooth cells become dysfunctional, they begin to proliferate and remodel the blood vessel to make it stiffer by degrading elastin and depositing collagen. While this transition is well established, the mechanisms that trigger smooth muscle cells to change and stiffen arteries is not understood. This research hypothesizes that this vascular smooth muscle cell dysfunction is mediated by the adipose (fat) tissue that is present surrounding the arteries. This fat, known as perivascular adipose tissue, directly surrounds large blood vessels, where it produces and releases factors that have recently been shown to impact the blood vessel wall. The goal of this project is to investigate how perivascular adipose tissue inflammation and sympathetic nervous system activity impact aortic stiffening. The research team will determine how perivascular adipose tissue impacts vascular smooth muscle cell function (phenotype) in both an artery-on-a-chip and in spinal cord injured mice. Spinal cord injury is an interesting model for arterial stiffening, since patients with chronic spinal cord injury have stiffer arteries despite normal blood pressure. Knowledge gained through this project could lead to improved diagnostic and treatment strategies for arterial stiffening and cardiovascular disease. In addition, this project will expand the opportunities available for undergraduate students to participate in research experiences. Specifically, the research team will incorporate this research project into a Course-based Undergraduate Research Experience (CURE), in which the entire class addresses a research question of interest to the scientific community. This course will then be translated into educational cardiovascular biomechanics modules for high school students.Two research objectives have been established to support this project. First, the work will determine how perivascular adipose tissue inflammation contributes to arterial stiffening. Using a mouse model of spinal cord injury, the research will quantify changes in arterial stiffness, perivascular adipose tissue inflammation, expression and activity of MMP-12 (an enzyme that degrades elastin), as well as elastin content and fragmentation. Second, the researchers will determine how sympathetic nervous system activity associated with perivascular adipose tissue contributes to arterial stiffening. A similar mouse model with spinal cord injury will be used to quantify changes in arterial stiffness, perivascular adipose tissue sympathetic nervous system activity, vascular smooth muscle cell proliferation, arterial thickness, and collagen content. An artery-on-a-chip model will be used to support both objectives by determining how adipokines secreted by perivascular adipose tissue, when it is either inflamed or stimulated by norepinephrine, affects vascular smooth muscle cells as well as how endothelial cells may mediate this effect. In addition, two educational objectives will introduce cardiovascular engineering to undergraduate and high school students through course-based research activities as well as outreach modules.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

动脉硬化是导致血管疾病的重要因素，血管疾病会导致高血压、心血管疾病、中风和其他重大疾病。动脉僵硬在很大程度上取决于血管平滑肌细胞的功能。当血管平滑细胞功能失调时，它们开始增殖和重塑血管，通过降解弹性蛋白和沉积胶原蛋白使血管变得更坚硬。虽然这一转变已得到很好的证实，但触发平滑肌细胞改变和使动脉硬化的机制尚不清楚。这项研究假设，这种血管平滑肌细胞功能障碍是由动脉周围存在的脂肪组织介导的。这种脂肪被称为血管周围脂肪组织，它直接围绕着大血管，在那里产生和释放最近被证明影响血管壁的因子。该项目的目标是调查血管周围脂肪组织炎症和交感神经系统活动如何影响主动脉僵硬。研究小组将确定血管周围脂肪组织如何影响芯片上动脉和脊髓损伤小鼠的血管平滑肌细胞功能(表型)。脊髓损伤是动脉硬化的一个有趣的模型，因为慢性脊髓损伤的患者尽管血压正常，但动脉却更僵硬。通过该项目获得的知识可以改进动脉硬化和心血管疾病的诊断和治疗策略。此外，该项目还将扩大本科生参与研究体验的机会。具体地说，研究团队将把这一研究项目纳入以课程为基础的本科生研究体验(CURE)，在这一过程中，整个班级都会解决科学界感兴趣的研究问题。这门课程将被转化为高中生的心血管生物力学教学模块。为了支持这个项目，我们已经确定了两个研究目标。首先，这项工作将确定血管周围脂肪组织炎症如何导致动脉硬化。利用小鼠脊髓损伤模型，这项研究将量化动脉僵硬、血管周围脂肪组织炎症、基质金属蛋白酶-12(一种降解弹性蛋白的酶)的表达和活性，以及弹性蛋白含量和碎裂的变化。其次，研究人员将确定与血管周围脂肪组织相关的交感神经系统活动如何有助于动脉硬化。类似的脊髓损伤小鼠模型将用于量化动脉僵硬、血管周围脂肪组织交感神经系统活动、血管平滑肌细胞增殖、动脉厚度和胶原含量的变化。芯片上动脉模型将用于支持这两个目标，方法是确定血管周围脂肪组织在发炎或受到去甲肾上腺素刺激时分泌的脂肪因子如何影响血管平滑肌细胞，以及内皮细胞如何介导这一影响。此外，两个教育目标将通过基于课程的研究活动和外展模块向本科生和高中生介绍心血管工程。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。