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.
