Reversal of bone marrow mobilopathy and enhanced vascular repair by angiotensin-(1-7) in Diabetes

Goutham Vasam; Shrinidh Joshi; Sean E. Thatcher; Stephen H. Bartelmez; Lisa A. Cassis; Yagna P.R. Jarajapu

doi:10.2337/db16-1039

Reversal of bone marrow mobilopathy and enhanced vascular repair by angiotensin-(1-7) in Diabetes

Goutham Vasam, Shrinidh Joshi, Sean E. Thatcher, Stephen H. Bartelmez, Lisa A. Cassis, Yagna P.R. Jarajapu

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23 Scopus citations

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	https://doi.org/10.2337/db16-1039
State	Published - Feb 1 2017

Bibliographical note

Funding Information:
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).

Publisher Copyright:
© 2017 by the American Diabetes Association.

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism

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10.2337/db16-1039

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title = "Reversal of bone marrow mobilopathy and enhanced vascular repair by angiotensin-(1-7) in Diabetes",

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.",

author = "Goutham Vasam and Shrinidh Joshi and Thatcher, {Sean E.} and Bartelmez, {Stephen H.} and Cassis, {Lisa A.} and Jarajapu, {Yagna P.R.}",

note = "Funding Information: 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). Publisher Copyright: {\textcopyright} 2017 by the American Diabetes Association.",

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N2 - 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.

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Reversal of bone marrow mobilopathy and enhanced vascular repair by angiotensin-(1-7) in Diabetes

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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