Vascular 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. / American Heart Association grant, 13SDG16960025 / National Institutes of Health, National institute of Aging (NIA), 1R01AG056881
| Identifer | oai:union.ndltd.org:ndsu.edu/oai:library.ndsu.edu:10365/28961 |
| Date | January 2019 |
| Creators | Joshi, Shrinidh Ashokkumar |
| Publisher | North Dakota State University |
| Source Sets | North Dakota State University |
| Detected Language | English |
| Type | text/dissertation, movingimage/video |
| Format | application/pdf, video/mp4 |
| Rights | NDSU Policy 190.6.2, https://www.ndsu.edu/fileadmin/policy/190.pdf |
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