Vascular smooth muscle cells surround blood vessels and contract or relax to change the vessel diameter during healthy cardiovascular function. Recent studies have shown that the layer of fat surrounding most blood vessels, called perivascular adipose tissue (PVAT), may modulate vascular contractility. In healthy subjects, PVAT relaxes the adjacent blood vessel, making it easier for blood to flow. However, in diseases such hypertension and atherosclerosis, PVAT may cause the blood vessels to constrict. While blood vessel constriction and dilation can be measured in humans and animals, it is difficult to study the effects of PVAT on the blood vessels in these models. The investigator's long-term goal is to understand how PVAT affects arterial function in health and disease. The goal of this project is to create an artery-on-a-chip model that enables measurement of vascular contractility and could in the future be integrated with PVAT. Specifically, the project will create an artery using micro- and nano-ribbons to align contractile vascular smooth muscle cells circumferentially around a hollow channel. The inside of the channel will then be lined with endothelial cells. The artery-on-a-chip device will be validated using biochemical assays and comparisons to mouse blood vessel measurements and to human studies. The artery-on-a-chip can then be used for drug testing and in the future to improve understanding of how changes in PVAT affect vascular function. In addition, opportunities for undergraduate students to participate in research experiences will be expanded. Specifically, the research project will be incorporated into a Course-based Undergraduate Research Experience (CURE), in which the entire class addresses a research question of interest to the scientific community. Components of the course will then be translated into cell and organ level modules for high school students attending a Biomed Summer Academy.
The project is focused on creating an artery-on-a-chip that enables vascular contractility measurements in response to mechanical and biochemical stimuli. Vascular contractility, which is essential to blood pressure regulation, blood distribution and injury response, is mediated by vascular smooth muscle cells (vSMC) and perivascular adipose tissue(PVAT). While PVAT is known to exert an anti-contractile effect on the adjacent vasculature in healthy conditions and to lose its anti-contractile effect in diseases such hypertension, atherosclerosis, aneurysm and obesity, most of the evidence linking PVAT to vascular disease remains correlative because there are few ways to specifically manipulate PVAT without affecting the other adipose depots or the vessel itself. Current in vitro arterial systems do not incorporate PVAT and few enable vascular contractility measurements. The artery-on-a chip platform developed in this project will address this need by achieving two objectives. The FIRST Objective is to create an endothelialized tube of circumferentially aligned, contractile vSMCs. Studies are designed to explore how aligned micro- and nano-ribbons can create an aligned endothelialized vSMC syncytium in a cylindrical channel and to determine the effect of micro- and nano-ribbons composition and mechanical properties on vSMC vasoconstriction and vasodilation. The artery-on-a-chip will be validated using mouse artery pressure myography and human vasoreactivity data. The SECOND Objective is to determine how to measure 3D traction forces generated by vSMC using the unique properties of the micro and nano-ribbons. The vSMC contractile measurements will be compared to artery-on-a-chip constriction and will be validated using mouse artery pressure myography and human vasoreactivity data. This research will be the first to create a human artery-on-a-chip to test vascular contractility with future potential to incorporate PVAT.
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.
