Investigating the Interplay Between Endothelial BMPR2 Loss, Interleukin-15 Signaling, and Sex Hormones in the Pathogenesis of Pulmonary Arterial Hypertension
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Authors
Hilton, Rhiannon
Date
Type
thesis
Language
eng
Keyword
PAH , NK Cells , BMPR2 , Sex Differences
Alternative Title
Abstract
Pulmonary arterial hypertension (PAH) is a disease of occlusive vascular remodeling, resulting in increased resistance in the lungs vasculature, progressive decrease in cardiac output, and eventually death from right heart failure within 3-5 years of diagnosis if left untreated. PAH is strongly associated with mutations in the gene encoding the type-II bone morphogenetic protein receptor (BMPR2), female sex, and immune dysfunction. However, the molecular mechanisms by which these factors contribute to disease development, or the interplay between them, remains poorly understood.
The work presented in this thesis explores how the loss of interleukin-15 (IL-15), a major homeostatic regulator of natural killer (NK) cells, contributes to disease development in two major rat models of PAH. Additionally, this work examines how endothelial BMPR2 loss impacts IL-15 signaling in vitro and examines how endothelial Bmpr2 loss in mice impacts their circulating immune phenotype. Finally, this work assesses the impact of gonad-derived sex hormones on disease severity in NK cell-deficient Il15 knockout (Il15-/-) rats in disease.
These studies demonstrate that loss of IL-15 and NK cells exacerbates disease in experimental models of PAH. Additionally, this work shows that the loss of endothelial BMPR2 results in decreased surface presentation and secretion of the major IL-15 receptor (IL-15Ra) via impaired trafficking through the trans-Golgi network (TGN). Finally, studies assessing the effects of gonad-derived sex hormones on disease severity demonstrate a novel interplay between NK cells and estrogen in right ventricular remodeling. The presented work highlights previously unappreciated links between the genetic basis of PAH, NK cells, and sex hormones in both pulmonary vascular and right ventricular remodeling in PAH.
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ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.