Mechanisms of vascular dysfunction in obesity and type 2 diabetes: role of the gut microbiota and endoplasmic reticulum stress
Date
2018
Authors
Battson, Micah Lee, author
Gentile, Christopher, advisor
Cox-York, Kimberly, advisor
Weir, Tiffany, committee member
Pagliassotti, Michael, committee member
Chicco, Adam, committee member
Journal Title
Journal ISSN
Volume Title
Abstract
Vascular dysfunction, characterized by arterial stiffness and endothelial dysfunction, is a key antecedent to overt cardiovascular disease in obesity and type 2 diabetes. Although the mechanisms underlying the development of vascular dysfunction in obese and type 2 diabetic individuals are not fully known, a growing body of evidence suggest that adverse cellular processes, including endoplasmic reticulum (ER) stress, inflammation and oxidative stress, are primarily responsible for the disruption of normal vascular function in these two metabolic diseases. Therefore, identifying effective strategies to mitigate one or more of these adverse processes may lead to novel therapies for the treatment of vascular dysfunction in obesity and/or type 2 diabetes. In addition, ascertaining the initial triggering factor(s) that promote these adverse processes will inform innovative ways to prevent or control the progression of vascular dysfunction. The goals of this dissertation research were to 1) examine the underlying causes of vascular dysfunction in obesity and type 2 diabetes and 2) identify potential strategies to mitigate vascular dysfunction in these metabolic diseases. To this end, we conducted three separate studies in murine models of obesity and/or type 2 diabetes aimed to modulate key factors that can affect vascular function. In all three studies, we measured aortic pulse wave velocity and endothelium-dependent dilation as clinically relevant indices of arterial stiffness and endothelial dysfunction, respectively. We also conducted various biochemical analyses to explore the potential mechanisms by which our experimental interventions altered vascular function. In our first study (Chapter 2), we examined the role of ER stress in diabetic vascular dysfunction. In type 2 diabetic (db/db) mice, we found that chronic administration of the ER stress inhibitor, tauroursodeoxycholic acid (TUDCA), significantly reduced arterial stiffness and endothelial dysfunction. These vascular improvements were associated with reduced expression of ER stress-related genes within the aorta and surrounding perivascular adipose tissue (PVAT). Next (Chapter 3), we examined the role of the gut microbiota in the development of vascular dysfunction in obesity. We found that Western diet (WD)-induced obesity increased arterial stiffness, impaired endothelial function, and promoted endotoxemia-related inflammation. Antibiotic treatment to suppress the gut microbiota in WD-fed mice reduced arterial stiffness, improved endothelial function, and attenuated systemic and vascular inflammation. In our final study (Chapter 4), we examined whether gut dysbiosis represents a causal factor in the development of obesity-related vascular dysfunction. We found that transplant of gut microbiota from obese (ob/ob) to control mice promoted the development of arterial stiffness, and this was associated with reduced abundance of a symbiotic bacterium, Akkermansia muciniphila, decreased short-chain fatty acid levels, and increased gut permeability. In contrast, transplant of control microbiota to obese mice did not attenuate arterial stiffness. Collectively, these studies in mice provided evidence that 1) mitigation of ER stress improves vascular function in type 2 diabetes, 2) gut dysbiosis contributes to vascular dysfunction in WD-induced obesity, and 3) an obese-type microbiota can promote arterial stiffening independent of body weight. Future clinical trials and mechanistic studies are needed to translate our findings to humans and to further examine the molecular mechanisms linking gut dysbiosis to vascular dysfunction.