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dc.contributor.authorJoshi, Shrinidh Ashokkumar
dc.description.abstractVascular disease is the leading cause of mortality and morbidity in the western world, and account for the 1 of every 3 death’s in the US, but a cure for vascular disease is yet to be realized. Hematopoietic stem progenitor cells (HSPCs) are mobilized from bone marrow and have the innate propensity to accelerate vascular repair by reendothelialization and revascularization of ischemic areas. The vasoreparative ability of HSPCs is largely due to their capacity to home to the areas of hypoxia and their sensitivity to hypoxia plays a critical role in the vasoreparative functions of these cells. The discovery of vasoreparative potential of HSPCs resulted in a breakthrough approach of cell-based therapies for the treatment of ischemic vascular diseases. However, success of this approach is essentially dependent on the number of cells that could be collected from an individual. Therefore, novel mechanism-based strategies are needed to enhance the outcomes of autologous cell-based therapies in poor mobilizers and older adults. Recent evidence of a potential role of the vasoprotective axis of the renin angiotensin system (RAS) in HSPCs functions offers a breakthrough. Angiotensin-(1-7), the primary mediator of the protective functions which acts on Mas receptor (MasR), is generated by angiotensin converting enzyme-2 (ACE2). In this study, we tested the effects of hypoxia on stimulation of vasoreparative potential of HSPCs and in upregulation of ACE2 and MasR. Importantly, we delineated the molecular mechanism of hypoxic exposure in regulation of ACE2 and MasR in a HIF1α- dependent manner and hypoxic exposure induced shedding of the membrane bound ACE2 in HSPCs. We used luciferase, a reporter assay, cell-based assays, gene/protein expression studies and pharmacological strategies in human and mouse HSPCs to test our hypotheses. To verify the biological significance of hypoxia, we performed in vivo studies in mice and humans, which recapitulated the in vitro observations on vascular protective axis of RAS in HSPCs. Collectively, these studies provided mechanistic insights into hypoxic regulation of vascular protective axis of RAS in HSPCs and also provided compelling evidence for the clinical use of hypoxia as a promising approach for enhancing the vasoreparative outcomes of cell-based therapies.en_US
dc.publisherNorth Dakota State Universityen_US
dc.rightsNDSU Policy 190.6.2
dc.titleHypoxic Regulation of Angiotensin-Converting Enzyme 2 and Mas Receptor in Hematopoietic Stem/Progenitor Cells: A Translational Studyen_US
dc.typeDissertationen_US
dc.typeVideoen_US
dc.date.accessioned2018-11-14T14:36:48Z
dc.date.available2018-11-14T14:36:48Z
dc.date.issued2019en_US
dc.identifier.urihttps://hdl.handle.net/10365/28961
dc.subjectACE2en_US
dc.subjectblood flow restrictionen_US
dc.subjectCD34+ cellsen_US
dc.subjecthypoxiaen_US
dc.subjectMas receptoren_US
dc.subjectstem cellsen_US
dc.title.alternativeHypoxic Stimulation of Vasoreparative Functions in Human CD34+ cells are Mediated by Angiotensin Converting Enzyme-2 and Mas Receptoren_US
dc.identifier.orcid0000-0001-5406-2256
dc.description.sponsorshipAmerican Heart Association grant, 13SDG16960025en_US
dc.description.sponsorshipNational Institutes of Health, National institute of Aging (NIA), 1R01AG056881en_US
dc.rights.urihttps://www.ndsu.edu/fileadmin/policy/190.pdf
ndsu.degreeDoctor of Philosophy (PhD)en_US
ndsu.collegeHealth Professionsen_US
ndsu.departmentSchool of Pharmacyen_US
ndsu.programPharmaceutical Sciences
ndsu.advisorJarajapu, Yagna


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