Abstract
The angiotensin (ANG)-(1-7)/Mas receptor (MasR) pathway activates vascular repair-relevant functions of bone marrow progenitor cells. We tested the effects of ANG- (1-7) on mobilization and vasoreparative functions of progenitor cells that are impaired in diabetes. The study was performed in streptozotocin-induced diabetic (db/db) mice. Diabetes resulted in a decreased number of Lineage2Sca-1+c-Kit+ (LSK) cells in the circulation, which was normalized by ANG-(1-7). Diabetes-induced depletion of LSK cells in the bone marrow was reversed by ANG-(1-7). r-Kinase (ROCK) activity was increased specifically in bone marrow LSK cells by ANG-(1-7) in diabetes, and the beneficial effects of ANG-(1-7) were prevented by fasudil. ANG-(1-7) increased Slit3 levels in the bone marrow supernatants, which activated ROCK in LSK cells and sensitized them for stromal-derived factor-1a (SDF)- induced migration. Diabetes prevented the mobilization of LSK cells in response to ischemia and impaired the recovery of blood flow, both of which were reversed by ANG-(1-7) in both models of diabetes. Genetic ablation of MasR prevented ischemia-induced mobilization of LSK cells and impaired blood flow recovery, which was associated with decreased proliferation and migration of LSK cells in response to SDF or vascular endothelial growth factor. These results suggest that MasR is a promising target for the treatment of diabetic bone marrow mobilopathy and vascular disease.
| Original language | English |
|---|---|
| Pages (from-to) | 505-518 |
| Number of pages | 14 |
| Journal | Diabetes |
| Volume | 66 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 1 2017 |
Bibliographical note
Publisher Copyright:© 2017 by the American Diabetes Association.
Funding
This study was partly supported by American Heart Association grant 13SDG16960025 and National Institutes of Health (NIH) grant R01-HL-073085. The Core Biology Facility at North Dakota State University was made possible by NIH grant P30-GM-103332-01 from the National Institute of General Medicine. NIH grants to Velocigene at Regeneron Inc. (U01-HG-004085) and the CSD Consortium (U01-HG-004080) funded the generation of gene-targeted embryonic stem cells for 8,500 genes in the KOMP, which were archived and distributed by the KOMP Repository at University of California, Davis, and Children's Hospital Oakland Research Institute (U42-RR-024244).
| Funders | Funder number |
|---|---|
| CSD Consortium | U01-HG-004080 |
| Children’s Hospital Oakland Research Institute | U42-RR-024244 |
| Regeneron Pharmaceuticals, Inc. | U01-HG-004085 |
| National Institutes of Health (NIH) | P30-GM-103332-01, R01-HL-073085 |
| National Human Genome Research Institute | U01HG004080 |
| National Institute of General Medical Sciences | |
| American Heart Association | 13SDG16960025 |
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism
