Blood Flow Regulates Atherosclerosis Progression and Regression

Authors

Morgan A. Schake, University of Nebraska–LincolnFollow

First Advisor

Ryan Pedrigi

Date of this Version

5-2023

Document Type

Article

Citation

Schake, Morgan A., Blood Flow Regulates Atherosclerosis Progression and Regression [dissertation]. [Lincoln]: University of Nebraska-Lincoln; 2023. 172 p.

Comments

A DISSERTATION Presented to the Faculty of The Graduate College at the University of Nebraska In Partial Fulfillment of Requirements For the Degree of Doctor of Philosophy, Major: Biomedical Engineering, Under the Supervision of Professor Ryan M. Pedrigi. Lincoln, Nebraska: May, 2023

Copyright © 2023 Morgan A. Schake

Abstract

Atherosclerosis is the most prevalent pathology of cardiovascular disease with no known cure. Despite the many systemic risk factors for atherosclerosis, plaques do not form randomly in the vasculature. Instead, they form around bifurcations and the inner curvature of highly curving arterial segments that contain so-called disturbed blood flow that is low in magnitude and multidirectional over the cardiac cycle. Conversely, straight, non-bifurcated arterial segments that contain moderate-to-high and unidirectional (i.e., normal) blood flow are protected from plaque development. Thus, blood flow is a key regulator of atherosclerosis that may be able to be leveraged to develop new therapeutics. Towards this end, we performed two studies using a mouse model of atherosclerosis where a blood flow-modifying cuff was placed around the left carotid artery to induce disturbed blood flow and, in turn, plaque development. In the first study, we evaluated the hypothesis that injected nanoparticles had different accumulation kinetics in different types of disturbed flow (low versus multidirectional). We found that the blood flow profile did not affect accumulation, but the resultant plaque phenotype did. This suggests that nanoparticles could be used to target certain plaque types. In the second study, we evaluated the hypothesis that restored normal blood flow in atherosclerotic arteries promotes plaque stabilization. Our findings supported this hypothesis and also showed that the combination of normal blood flow and atorvastatin produced additive beneficial effects that led to plaque regression. This result suggests that mechanical stimuli can be therapeutic. Since the endothelium directly senses blood flow and plays a key role in atherosclerosis development, we finally characterized how different flow profiles affect atheroprotective versus atherogenic endothelial signaling molecules. Ultimately, this work provides a foundation for the development of a new therapeutic for atherosclerosis based on the beneficial effects of normal blood flow.

Advisor: Ryan M. Pedrigi