All ETDs from UAB

Advisory Committee Chair

Jennifer S Pollock

Advisory Committee Members

Michelle V Fanucchi

Tim M Townes

Victor M Darley-Usmar

Daniel I Feig

David M Pollock

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Psychosocial stress occurs in response to threatening or uncertainty-provoking stimuli and triggers a complex physiological reaction that facilitates survival and adaptation. In the cardiovascular system, acute psychosocial stress elicits a rapid increase in blood pressure, and importantly, cumulative exposure to psychosocial stress is a risk factor for cardiovascular disease. The present studies examined the impact of psychosocial stress on the cardiovascular system in both health and disease. Circulating endothelin-1 (ET-1) levels are induced by psychosocial stress. We hypothesized that endothelium-derived ET-1 contributes to the pressor response to stress via activation of the endothelin A (ETA) receptor. Vascular endothelium-specific ET-1 knockout (VEETKO) and control (flox) mice were exposed to cage switch stress (CSS), a model of psychosocial stress. A pressor response was elicited by CSS in both genotypes; however, this response was blunted in VEETKO compared to flox mice. In mice pretreated with the ETA receptor antagonist, ABT-627, the pressor response to CSS was similar between genotypes. CSS increased plasma ET-1 levels in flox, but in VEETKO mice CSS failed to elicit an increase in plasma ET-1. These findings specify that acute stress-induced activation of endothelium-derived ET-1, and subsequent ETA receptor activation, is a novel mediator of the blood pressure response to acute psychosocial stress. Psychosocial stress has been linked to the onset of vaso-occlusive pain crises in sickle cell disease (SCD) patients. We hypothesized that acute psychosocial stress induces plasma histamine levels leading to a blunted diastolic blood pressure response to stress in SCD mice. Humanized sickle cell disease (HbSS) or control (HbAA) mice were treated with vehicle or H1 and H2 receptor antagonists and exposed to CSS. In response to CSS, plasma histamine was elevated in HbSS, but not HbAA mice. The peak mean arterial blood pressure response to CSS was blunted in vehicle treated HbSS versus HbAA mice, and this effect was driven by lower diastolic pressure, but not systolic pressure. Following combined H1 and H2 receptor antagonism, the peak blood pressure response in HbSS mice was restored to HbAA levels. Thus, in SCD mice, histamine functions as a novel mediator of the blood pressure response to stress.

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