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Role of Disintegrin and Metalloproteinase 17 (ADAM17) in Hypertension and Thoracic Aortic Aneurysm

  • Author / Creator
    Shen, Mengcheng
  • Hypertension is a major risk factor for cardiovascular complications such as stroke, myocardial infarction, heart failure, and renal failure, and therefore is an enormous healthcare burden worldwide. The renin-angiotensin system (RAS) is an essential regulator of blood pressure homeostasis, and angiotensin II (Ang II), the primary effector peptide of the RAS, plays a crucial role in acute and long-term regulation of blood pressure predominantly through the Ang II receptor type I (AT1). Although blockade of the RAS has been a mainstay in the treatment for hypertension and its complications, novel candidates in mediating the Ang II-induced hypertension and end-organ damage continue to be discovered. Thoracic aortic aneurysm (TAA), another vascular complication, is a permanent dilation and structural weakening of the thoracic aorta that predisposes to the fatal consequences of aortic dissection or rupture. Although efforts have been devoted to determining the molecular and pathophysiological characteristics of TAA, the underlying mechanisms for TAA initiation and development are still largely unknown. Currently, there is no treatment available for this disease, and surgical repair is the only option to treat advanced TAA. A disintegrin and metalloproteinase-17 (ADAM17) is a membrane-bound protease that proteolytically processes a variety of multifunctional cell surface molecules to regulate cell growth, proliferation, migration, differentiation, apoptosis, angiogenesis and neovascularization, inflammation, ECM remodeling, inflammatory cell adhesion, recruitment and transmigration, and vascular barrier integrity. The research presented in this dissertation identified the role of smooth muscle cell (SMC)- and endothelial cell (EC)-specific ADAM17 in Ang II-induced hypertension and end-organ damage, as well as in the pathogenesis of TAA. In vitro, Adam17-deficiency did not alter the cell morphology or basal levels of SMC contractile proteins, but significantly suppressed Ang II-induced proliferation and migration in these cells. By infusing Ang II in SMC-Adam17-intact and SMC-Adam17-deficient mice for 2 and 4 weeks, we observed a transient protection of Ang II-induced hypertension, cardiac and renal hypertrophy and fibrosis in SMC-Adam17-deficient mice, which were abolished with prolonged Ang II infusion. Ex vivo vascular function and compliance assessed in mesenteric arteries were comparable between genotypes. Mechanistic studies showed that EGFR signaling from other vascular cell types (e.g., fibroblasts) might compensate for the loss of biological functions of ADAM17 in SMCs. An optimized periadventitial elastase-injury induced TAA model was used to explore the role of vascular ADAM17 in the progression of TAA. Both SMC- and EC-deficiency of Adam17 mitigated elastase-induced TAA, however, in vitro studies revealed that ADAM17 in SMCs and ECs played distinct roles in the pathogenesis of TAA. In response to elastase-induced injury, Adam17-deficiency in SMCs prevented contractile-to-synthetic phenotypic switching in these cells, thereby preventing perivascular fibrosis, inflammation, and adverse aortic remodeling. In comparison, Adam17-deficiency in ECs protected the integrity of the intimal barrier by preserving the junction protein complex, which consequently led to the suppression of inflammatory cell infiltration into the aortic wall. In line with the findings observed in genetically modified mice, an ADAM17-selective inhibitor showed protective effects on TAA formation as well as growth. In summary, the research described in this dissertation demonstrated that Adam17-deficiency in SMCs is not sufficient to suppress Ang II-induced hypertension and end-organ damage. Whereas in TAA, ADAM17 plays cell-specific functions in disease progression by promoting pathological remodeling of SMC and impairing the integrity of intimal EC barrier. The protective role of genetic and pharmacological inhibition of ADAM17 in attenuating the progression of TAA highlighted the unique position of this protease as a potential treatment target for TAA.

  • Subjects / Keywords
  • Graduation date
    Fall 2018
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3R78650V
  • License
    Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.