Thursday, April 3, 2025
4/3/2025
Stress-Induced Signaling in Aortopathy - In 2018, roughly 74% of people reported psychological stress within the past year. Chronic psychological stress has been associated with increased risk for developing cardiovascular disease and hypertension, however the exact mechanism linking the two is unknown. Patients with post-traumatic stress disorder (PTSD), a disorder of extreme stress, have higher heart rates and blood pressures as well as an increased prevalence of resistant hypertension. Resistant hypertension is likely neurogenically derived as stress-induced changes in blood pressure are mediated, in part, by an amygdala-hypothalamic pathway contributing to sympathetic overactivation. This pathway is regulated by inhibitory GABA-ergic circuits. Elevations in blood pressure have been shown to influence extracellular matrix (ECM) remodeling leading to disruption of aortic wall homeostasis and increased vascular fibrosis predisposing to aortic pathology such as aortic aneurysms. Allopregnanolone is a neurosteroid that functions as a positive allosteric modulator of the GABAA receptor and has been shown to reverse neurogenic hypertension and treat PTSD symptoms in both animal and human studies. Our lab has demonstrated that mice with generalized anxiety and neurogenic hypertension exhibit elevated medial collagen and collagen cross-linking, and decreased thoracic aortic compliance. Additionally, these mice have an accelerated rate of thoracic aortic aneurysm progression demonstrating a predisposition to vascular pathology. Furthermore, our lab has developed a PTSD-like mouse model that exhibits higher blood pressure that is renin independent, elevated medial collagen, and increased thoracic aortic stiffness. Importantly, PTSD mice that underwent thoracic aortic aneurysm induction displayed an accelerated rate of aneurysm development. Thus, we hypothesize that stress-dependent hypertension alters homeostatic ECM remodeling which can accelerate vascular pathology. This hypothesis will be tested using two mouse models, a generalized anxiety model and a PTSD model. Aim 1 will investigate the determinants of stress-induced ECM remodeling by examining the role of sympathetic overactivation in neurogenic hypertension, the mechanism of TGF-b signaling driving stress-induced ECM remodeling, and novel signaling pathways directing stress-induced ECM remodeling through bulk RNA sequencing. Aim 2 will demonstrate that allopregnanolone, a novel therapeutic, can suppress stress-induced neurogenic hypertension and acceleration of aortic pathology. Following allopregnanolone administration to both mouse models, attenuation of sympathetic overactivation, stress-induced ECM remodeling, and thoracic aortic aneurysm acceleration will be determined. Preliminary data has demonstrated the expression of the GABAA receptor in the thoracic aorta. Thus, local effects of allopregnanolone on contractility and relaxation will be examined. Results from this proposal will increase our understanding of the link between stress and aortopathy as well as the development of a novel therapeutic. In addition, this fellowship will provide me with training in cutting-edge techniques that will support my development as a surgeon-scientist.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).