| dc.contributor.author | Vasam, Goutham | |
| dc.description.abstract | Bone marrow stem/progenitor cells (BMPCs) accelerate vascular repair by re-endothelialization and revascularization of ischemic areas. Diabetes causes impairment of BMPC mobilization, a.k.a. stem cell mobilopathy, and reparative functions, which have now been considered as a major contributing factor for the development of macro and microvascular complications and end-organ damage. Therefore, autologous cell therapies for the treatment of diabetic vascular complications are currently not possible. In this study, I tested the effects of Angiotensin (Ang)-(1-7), a heptapeptide member of the protective arm of renin-angiotensin system, on mobilization of BMPCs and their ischemic vascular repair functions that are impaired in diabetes. Streptozotocin-induced diabetic or db/db mice were used. Circulating and bone marrow Lineage- Sca1+ c-Kit+ (LSK) cells were decreased in diabetes, which was normalized by Ang-(1-7). Ang-(1-7) specifically increases Rho-kinase (ROCK) activity in diabetic bone marrow (BM) LSK cells, and fasudil, a ROCK inhibitor, prevented the beneficial effects of Ang-(1-7). BM Slit3 levels were increased by Ang-(1-7), which might have activated ROCK in LSK cells and sensitized for stromal-derived factor-1 (SDF)-induced migration. In relation to ischemia, diabetes prevented LSK cell mobilization and blood flow recovery, which were reversed by Ang-(1-7). Ang-(1-7), in combination with G-CSF or plerixafor reversed the stem cell mobilopathy in diabetes. These beneficial effects of Ang-(1-7) were blunted in Mas receptor knockout (MasR-KO) mice. These results suggest that MasR is a promising target for the treatment of diabetic bone marrow mobilopathy and vascular disease. Overall, this study provided strong preclinical evidence, supporting Ang-(1-7) as a promising molecule for the treatment of diabetic stem cell mobilopathy and vascular disease. | en_US |
| dc.publisher | North Dakota State University | en_US |
| dc.rights | NDSU Policy 190.6.2 | |
| dc.title | Angiotensin-(1-7): A Target for Stem Cell Mobilopathy and Vascular Repair in Diabetes | en_US |
| dc.type | Dissertation | en_US |
| dc.type | Video | en_US |
| dc.date.accessioned | 2018-05-22T16:20:34Z | |
| dc.date.available | 2018-05-22T16:20:34Z | |
| dc.date.issued | 2017 | en_US |
| dc.identifier.uri | https://hdl.handle.net/10365/28144 | |
| dc.identifier.orcid | 0000-0003-1733-3189 | |
| dc.description.sponsorship | American Heart Association (13SDG16960025) | en_US |
| dc.description.sponsorship | COBRE Pilot Project Grant (Intramural) | en_US |
| dc.description.sponsorship | Center for Protease Research (P30 GM103332 – 01). | en_US |
| dc.rights.uri | https://www.ndsu.edu/fileadmin/policy/190.pdf | |
| ndsu.degree | Doctor of Philosophy (PhD) | en_US |
| ndsu.college | Health Professions | en_US |
| ndsu.department | School of Pharmacy | en_US |
| ndsu.program | Pharmaceutical Sciences | |
| ndsu.advisor | Jarajapu, Yagna P.R. | |
