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Investigating the Endothelial PI3 Kinase Signalling Pathway in Vascular Repair

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Investigating the Endothelial PI3 Kinase Signalling Pathway in Vascular Repair Investigating the endothelial PI3 kinase signalling pathway in vascular repair by Maikel Farhan A thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Experimental Medicine Department of Medicine University of Alberta ©Maikel Farhan, 2016 Abstract Thrombotic microangiopathy (TMA) is a broad term for a range of diseases that usually manifest with rapid failure of the affected organ. Although different in etiology, these diseases share a common pattern of injury originating in the vascular endothelium. In turn, the injured vasculature elicits a physiological response in a trial to repair the damage. Accumulating evidence support the significance of vascular repair but the key regulators, and the underlying mechanism are still elusive. We have shown before that key aspects of the genetic programming involved in angiogenesis are required for vascular repair. In this thesis: First, we characterized the PI3K/AKT pathway, the main angiogenic pathway, outputs in the endothelial cell (EC). We approached the pathway at three different levels; upstream (mTORC2), midstream (Akt) and downstream (mTORC1). Our results indicate sustained inactivation of mTORC1 activity, up- regulated mTORC2-dependent Akt1 activation. In turn, ECs exposed to mTORC1-inhibition were resistant to apoptosis and hyper-responsive to renal cell carcinoma (RCC)-stimulated angiogenesis after relief of the inhibition. Conversely, mTORC1/2 dual inhibition or selective mTORC2 inactivation inhibited angiogenesis in response to RCC cells and vascular endothelial growth factor (VEGF). mTORC2-inactivation decreased EC migration more than Akt1- or mTORC1-inactivation. Mechanistically, mTORC2 inactivation robustly suppressed VEGF- stimulated EC actin polymerization, and inhibited focal adhesion formation and activation of focal adhesion kinase, independent of Akt. We concluded mTORC2 may have a superior role to Akt and mTORC1 in angiogenesis and vascular repair. Second, we identified the role of Facio-genital dysplasia-5 (FGD5) in regulation of the PI3K/AKT pathway. FGD5 is selectively expressed in EC and was reported to regulate angiogenesis. FGD5 deficiency reduced the number of angiogenic sprouts and their filopodia. ii These defects were accompanied by down regulation of tip cell-specific markers. FGD5 inactivation led to a decrease in EC migration and early protrusion (lamellipodia) formation. In resting, as well as VEGF-stimulated, EC, FGD5 formed a complex with VEGFR2 and was enriched at the leading edge of the cells and among endosomes. Further, FGD5 loss decreased endosomal VEGFR2 coupling to PI3K and diverted VEGFR2 to lysosomal degradation. This indicates FGD5 regulates VEGFR2 retention in recycling endosomes and coupling to PI3K/mTORC2-dependent cytoskeletal remodeling. Third, we investigated the role of FGD5 in regulation of G protein-coupled receptors (GPCRs) signaling. GPCRs operate in conjunction with VEGFR2 to activate PI3K pathway. We showed dual stimulation of GPCRs and VEGFR2 had synergic effect on angiogenesis. FGD5- loss abolished the GPCRs angiogenic effect and signaling to PI3K. Cdc42 inhibition, a RHO GEF required for PI3K activity, recapitulated the same signaling defects of FGD5 deficiency indicating that FGD5 may control PI3K activity through Cdc42. Subcellular localization of PI3K and its downstream Akt showed no change in PI3K localization to the early endosomes in case of FGD5 deficiency. However, failure of recruitment of active Akt to the PI3K positive endosomes suggests a defect in PI3K activity after FGD5 loss. This study investigated a novel role of FGD5 in regulating GPCRs signaling to PI3K, and suggests FGD5 as a convergence node regulating multiple angiogenic pathways that can spark hope for novel anti-angiogenic therapy. Finally, we studied vascular injury in animal model of chronic allograft vasculopathy (CAV). We showed that deficiency of Apelin, a peptide involved in angiogenesis that signals through PI3K in the endothelium, accelerated the vascular lesions in CAV and markedly affected iii the function of the transplanted grafts. This indicated that apelin may protect against the vascular injury produced in CAV. In summary, this work identifies potential targets that can regulate angiogenesis and vascular repair; and expands our understanding of the underlying mechanisms involved in angiogenesis. Further, it suggests novel candidates for antiangiogenic therapy to regulate pathological angiogenesis. iv Preface Some of the research conducted for this thesis forms part of existing publication and a submitted manuscript. The third chapter is published in PLoS one journal as “Farhan, M. A., Carmine- Simmen, K., Lewis, J. D., Moore, R. B., & Murray, A. G. (2015). Endothelial cell mTOR complex-2 regulates sprouting angiogenesis” with a doi number (10.1371/journal.pone.0135245). The fourth chapter is submitted to the ATVB journal with an ID (ATVB/2016/307495) as “Farhan M., Azad A., Nicolas T. and Allan G. Murray. Facio-genital dysplasia-5 (FGD5) regulates VEGF receptor-2 coupling to PI3 kinase and trafficking” and is currently under revision at the time of writing. The animals used in this project were maintained according to the Canadian Council for Animal Care (CCAC) guidelines under a protocol approved by the Animal Care and Use Committee of the University of Alberta. v Acknowledgement This work would have never finish without the tremendous support of my wife Sylvia Kalainy. You were always next to me when I needed you. No word can describe your dedication and love. To my beloved family, my father Adel Aziz Farhan, my mother Sonia Kromer Zakhary, and my brother Mina Farhan. Each one of you has a print in my life that changed me to what I am now. I learned from my father how to take care of my family and how to work hard to achieve my goals. My mother was the first person to show me how to study and she made me love knowledge. My brother was the voice of wisdom that convinced me to seek graduate studies and he was the first to believe in me that I can finish a PhD degree. To my supervisor Dr Allan Murray. You were a friend before being a supervisor. Your guidance and support helped me not only through my PhD but also at the career level. You are a good leader and a great scientist. I hope I can be like you one day. I will never forget how you helped me and my wife and I hope I can pay you back a small part of what you did for me. To my committee members, Dr Nicolas Touret and Dr Sean McMurtry. Thank you for your mindful thoughts and your wonderful advice and feedback that helped me to improve myself. A special thanks to Dr Evangelos Michelakis who taught me critical thinking, and saw something special in me. He encouraged me to apply for residency in the University of Alberta to be a clinician scientist, and he offered me a great support. I would like also to thank all my lab members who were good listeners and wonderful preceptors. vi Table of Contents Chapter I: Introduction .............................................................................................................................. 1 1 Thesis outline ........................................................................................................................................ 1 1.1 Objectives ............................................................................................................................. 2 1.2 Contribution to knowledge ................................................................................................. 3 2 Developmental angiogenesis .......................................................................................................... 4 2.1 Sprouting Angiogenesis ........................................................................................................... 5 2.2 Intussusceptive Angiogenesis .................................................................................................. 7 3 Pathological angiogenesis (Tumor angiogenesis) .............................................................................. 7 4 The role of VEGFR2/PI3Kinase pathway in angiogenesis ............................................................... 8 4.1 VEGFR2/PI3Kinase ................................................................................................................. 8 4.2 AKT (Protein kinase B) ......................................................................................................... 12 4.3 Mammalian target of rapamycin (mTOR) .......................................................................... 13 5 VEGFR2 beyond ligand binding (receptor trafficking) ................................................................. 14 6 Therapeutics of angiogenesis............................................................................................................. 15 6.1 Cancer ..................................................................................................................................... 16 6.2 Ocular neovascularization ..................................................................................................... 17 6.3 Interferon alpha-2a to treat hemangiomas .......................................................................... 17 6.4 Rheumatoid arthritis ............................................................................................................. 18 7 Tumor resistance to antiangiogenic therapy (Tumor escape) ........................................................ 18 8 Potential candidates
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