Date of Award

Spring 5-1-2026

Embargo Period

5-1-2028

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Surgery

College

College of Medicine

First Advisor

Jeffrey Jones

Abstract

Chronic psychological stress is a known risk factor for cardiovascular disease (Cohen et al., 2009; Crum-Cianflone et al., 2014; Edmondson and von Kanel, 2017; Remch et al., 2018; Rosengren et al., 2004; Ryder et al., 2018; Scherrer et al., 2020). Patients with post-traumatic stress disorder (PTSD), a disorder of psychological stress, have elevated blood pressure and heart rate both at rest and in response to stimuli (Buckley and Kaloupek, 2001; Burg and Soufer, 2016; Coughlin, 2011). The mechanism linking psychological stress and cardiovascular disease is under investigation, however it has been proposed in the literature that stress-induced hypertension may result from sympathetic nervous system overactivation, hypothalamic pituitary adrenal (HPA) axis dysregulation, and/or systemic inflammation (Cohen et al., 2007; Dunlop and Wong, 2019; Lucini et al., 2005; Slusher and Acevedo, 2023; Steptoe and Kivimäki, 2012). Translatability of basic science research findings in the field of chronic psychological stress has been slow due to large variations in rodent models of psychological stress and PTSD (Richter-Levin et al., 2019). Regardless of the precise mechanism(s) driving stress-induced hypertension, the direct effects of psychological stress on aortopathy have yet to be elucidated.

Elevations in blood pressure have been shown to influence extracellular matrix (ECM) remodeling leading to disruption of aortic wall homeostasis and increased vascular stiffness predisposing to aortic pathology such as aortic aneurysms (Barnes and Gorin, 2011; Boczar et al., 2021; Gao et al., 2003; Kaess et al., 2012). Current standard of care anti-hypertensive medications do not target neurogenic causes of hypertension such as sympathetic overactivation or HPA axis dysregulation leaving patients with longstanding uncontrolled hypertension (Unger et al., 2020). Allopregnanolone is a neurosteroid that functions as a positive allosteric modulator of the GABAA receptor (ligand-gated chloride channel)  and has been shown to reverse neurogenic hypertension and treat PTSD symptoms in both animal and human studies (mengEvans et al., 2012; Meng et al., 2025; Misztal et al., 2020; Rasmusson et al., 2017; Richardson et al., 2026; Stevenson et al., 2017). Thus, allopregnanolone may be a candidate as novel therapeutic to treat both chronic psychological stress symptoms as well as stress-induced hypertension.

We hypothesized that stress-dependent hypertension alters homeostatic aortic ECM remodeling which can accelerate vascular pathology, and specifically thoracic aortic aneurysms (TAA). In order to address this hypothesis, this dissertation will focus on three objectives: 1) development of a robust and translatable analysis method to define PTSD-like phenotype in mice; 2) determine the physiological impact of chronic psychological stress on vascular ECM remodeling and aortopathy; 3) explore allopregnanolone as a novel therapeutic to delay the progression of stress-induced aortopathy.

Rights

Copyright is held by the author. All rights reserved.

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