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Endothelial Injury and Repair of the Chronic Allograft Vasculopathy of Heart Allografts
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- Author / Creator
- Masoud, Andrew G.
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Heart transplantation (HTx) is a life-saving intervention for patients with end-stage heart failure. Nonetheless, the development of Chronic Allograft Vasculopathy (CAV) limits the longevity of transplanted cardiac allografts and the survival of recipients. The pathogenesis of CAV begins with a sustained immune-mediated endothelial injury of the heart transplant supplying blood vessels. Subsequently, maladaptive vascular repair, occlusive arteriopathy, and eventual ischemia ensue. This sequence of pathological events leaves the heart allograft deprived of an adequate blood supply to fail in the long run.
Despite breakthroughs in heart failure management and immunosuppression of transplanted donor hearts, such a disease onslaught persists. A poorly defined repair response that may replicate the vascular endothelial program used during vascular development mitigates the immunological injury. Current research efforts aim at establishing a relationship between this vascular immune injury and CAV development or prognosis. Additionally, researchers investigate the embryonic vascular developmental endothelial phenotype to test its benefits in repairing the injured vasculature in the adult.
In the embryo, vascular endothelial cells (ECs) respond to molecular drivers of angiogenesis, such as the Vascular Endothelial Growth Factor (VEGF), by differentiating into specialized phenotypes. Such endothelial phenotypes are associated with the expression of unique genes to promote angiogenesis (e.g., the apelin gene-APLN) and execute various autocrine and paracrine functions. In adult blood-vessel networks, however, the role of developmental cues of angiogenesis that signal through the G protein-coupled receptors (GPCRs) to repair the established blood vessels is still elusive. Currently, no treatment exists for this occlusive CAV that injures conduit and branch arteries and is the lead cause of recipients’ death, even in the first year post-transplantation. Thus, it becomes critical to characterize targeted therapeutics to activate vascular endothelial repair (molecular) pathways to treat CAV.
We exploited a well-established humanized mouse model of heart transplantation chronic rejection that maintains good perfusion of blood to the transplanted heart allografts. We employed minor histocompatibility-mismatched heart transplants to elicit a smouldering alloimmune response against the allograft’s vascular endothelium. Such a preclinical model allows a better tracking and studying of the vascular compartmental phenotypic changes post-transplantation correlated with endothelial immune injury and repair on tissue and molecular levels.
In this thesis: First, we tried to elucidate the role of apelin, as an endothelial proangiogenic cue, to direct vascular repair following CAV immune injury. A better-defined vascular endothelial repair pathway (i.e., an apelin-apelin GPCR (ApelinR; formerly known as APJ) signalling axis) can preserve allografts’ function and longevity and vigour.
Second, we examined the potential functions of endothelial Phosphoinositide 3-Kinase beta (PI3Kβ) signalling molecule downstream of the apelin-ApelinR axis in regulating EC injury and repair responses of CAV. Hence, we can better evaluate the nature, modes of activation and outcomes of activating such a secondary molecule downstream of apelin when the immune injury progresses and vascular repair follows.
Third, we investigated the influence of inhibiting the rapid enzymatic degradation of endogenous apelin, caused by neutral endopeptidases/metalloproteases like neprilysin, in an attempt to confirm the advantages of maintaining functional levels of in-vivo apelin. This approach entails testing a clinically approved drug (i.e., Sacubitril) for trials on heart failure with reduced left ventricular ejection fraction with a potential therapeutic translation to benefit transplant patients with immune-provoked vascular injury.
In summary, this work identifies potential therapeutic targets that can regulate vascular repair signalling pathways under current investigation and vascular inflammation following immune injury while directing pro-angiogenesis signalling. It expands our understanding of the underlying molecular and cellular mechanisms involved in vascular immune injury repair in the allograft vascular endothelium. Further, it suggests repurposing clinically approved therapeutic candidates to hinder vascular immune injury and inflammation. For example, we tested the proteolysis-resistant apelin-receptor agonist synthetic analogue (APLN-17), the Phosphoinositide 3-Kinase (PI3Kβ) selective inhibitor (GSK2636771), as well as the Sacubitril to suppress CAV progression. Future research can exploit these therapeutic candidates to treat the adverse phenotypes of vascular inflammatory diseases (e.g., autoimmune vasculitis). -
- Subjects / Keywords
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- Graduation date
- Fall 2022
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- Type of Item
- Thesis
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- Degree
- Doctor of Philosophy
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- License
- This thesis is made available by the University of Alberta Library with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.