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Date of Award
2017
Publisher
North Dakota State University
Document Type
Dissertation
Degree Awarded
Doctor of Philosophy (PhD)
Program
Pharmaceutical Sciences
Department
School of Pharmacy
College
Health Professions
Faculty Advisor
Jarajapu, Yagna P.R.
Description
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.
Recommended Citation
Vasam, Goutham, "Angiotensin-(1-7): A Target for Stem Cell Mobilopathy and Vascular Repair in Diabetes" (2017). Pharmacy. 11.
https://digitalcommons.ndsu.edu/pharm/11
Rights
NDSU Policy 190.6.2
Rights Link
https://www.ndsu.edu/fileadmin/policy/190.pdf
Author ORCID Identifier
0000-0003-1733-3189
Handle Identifier
https://hdl.handle.net/10365/28144