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

动脉硬化是导致高血压、心血管疾病、中风和其他重大医疗状况的血管疾病的重要因素。动脉硬度在很大程度上由血管平滑肌细胞的功能决定。当血管平滑肌细胞变得功能失调时，它们开始增殖并通过降解弹性蛋白和沉积胶原蛋白来重塑血管，使其变得更硬。虽然这种转变已经很好地建立，但触发平滑肌细胞改变和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的脂肪组织介导的。这种脂肪被称为血管周围脂肪组织，直接包围着大血管，在那里它产生和释放最近被证明会影响血管壁的因子。本项目的目的是研究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硬化。研究小组将确定血管周围脂肪组织如何影响动脉芯片和脊髓损伤小鼠的血管平滑肌细胞功能（表型）。脊髓损伤是一个有趣的动脉硬化模型，因为慢性脊髓损伤患者尽管血压正常，但动脉硬化。通过该项目获得的知识可以改善动脉硬化和心血管疾病的诊断和治疗策略。 此外，该项目将扩大本科生参与研究经验的机会。具体来说，研究团队将把这个研究项目纳入一个基于课程的本科生研究经验（CURE），在这个课程中，整个班级都在讨论科学界感兴趣的研究问题。本课程将被翻译成高中学生的心血管生物力学教学模块。 首先，这项工作将确定血管周围脂肪组织炎症如何促进动脉硬化。 使用脊髓损伤的小鼠模型，该研究将量化动脉僵硬度，血管周围脂肪组织炎症，MMP-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片的变化。 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促进动脉硬化。 将使用具有脊髓损伤的类似小鼠模型来量化动脉硬度、血管周围脂肪组织交感神经系统活性、血管平滑肌细胞增殖、动脉厚度和胶原蛋白含量的变化。 动脉芯片模型将用于支持这两个目标，通过确定如何由血管周围脂肪组织分泌的脂肪因子，当它是发炎或刺激的去甲肾上腺素，影响血管平滑肌细胞，以及如何内皮细胞可能介导这种效果。 此外，两个教育目标将通过基于课程的研究活动以及推广模块向本科生和高中生介绍心血管工程学。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.