Thrombospondin-1 as a Modulator of Carotid Plaque Formation and Arterial Remodeling in an Atherogenic, Disturbed-Flow Mouse Model Restricted; Files Only
Tu, Michael (Spring 2023)
Abstract
Thrombospondin-1 (TSP-1) is a multifunctional extracellular glycoprotein that facilitates fibrosis through the activation of latent transforming growth factor-ꞵ (TGF-ꞵ). The TSP-1/TGF-ꞵ pathway contributes to arterial stiffening and atherosclerosis and is upregulated in response to factors such as increased blood glucose, disturbed blood flow, and oscillatory shear. This study aims to examine the role of TSP-1 on plaque formation and artery remodeling in an atherogenic TSP-1 knockout mouse model with disturbed carotid artery flow.
Both experimental (TSP-1 KO) and control (C57BL/6) groups underwent left-sided partial carotid ligation (PCL) at 12 weeks old. Atherogenic conditions were simulated by induction of hyperlipidemia via infection with a gain-of-function Pcsk9-AAV and initiation of a high-fat diet one week prior to PCL. Vessels were harvested 4 weeks after PCL, embedded in OCT and paraffin, frozen, and sectioned with thicknesses of 7-8 μm. Sections were stained, then imaged under a microscope. Quantification was performed in ImageJ.
Overall, results showed no significant differences between KO and control groups. However, male and female subgroup analyses showed male KO mice had a significantly smaller proportion of necrotic area (p=0.0024), and significantly larger inner and outer diameters (p=0.0023; p=0.0037) compared to controls. Female KO mice had significantly decreased lesion areas (p=0.0061) and significantly less CD68-positive percent area (p=0.0204) compared to the control. While these results support prior evidence that the absence of TSP-1 may improve plaque morphology, the differences interestingly varied between sexes.
Previous research in atherosclerosis supports our findings, although they have used different models of atherosclerosis. Research into genes and their expression that are associated with observed changes will be useful in fully mapping mechanisms, and understanding these pathways can influence the development of effective therapeutics.
Table of Contents
1 - Abstract
3 - Abbreviations
4- Introduction
6 - Methods
9 - Results
10 - Discussion
13 - Acknowledgements and Conflicts
14 - Works Cited
16 - Tables and Figures
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File download under embargo until 19 May 2025 | 2023-04-13 13:03:47 -0400 | File download under embargo until 19 May 2025 |
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