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 Lineage-Sca-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). ρ-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-1α (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.
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND.
authors.forename: Goutham
authors.initials: G
authors.lastname: Vasam
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND.
authors.forename: Shrinidh
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY.
authors.forename: Sean E
authors.initials: SE
authors.lastname: Thatcher
authors.affiliation: BetaStem Therapeutics, Inc., San Francisco, CA.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Bartelmez
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cassis
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND yagna.jarajapu@ndsu.edu.
authors.forename: Yagna P R
authors.initials: YP
authors.lastname: Jarajapu
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000803:Angiotensin I / Q000494:pharmacology*; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000503:physiopathology; D001853:Bone Marrow / Q000187:drug effects / Q000503:physiopathology; D001854:Bone Marrow Cells / Q000187:drug effects*; D019070:Cell Lineage; D002465:Cell Movement / Q000187:drug effects*; D054377:Chemokine CXCL12 / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D007511:Ischemia; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D020127:Recovery of Function / Q000187:drug effects; D012038:Regeneration; D013234:Stem Cells / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000187:drug effects / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D008565:Membrane Proteins; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; C432251:Slit3 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D014665:Vasodilator Agents; C467480:vascular endothelial growth factor A, mouse; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000803:Angiotensin I; D054460:rho-Associated Kinases; C118790:angiotensin I (1-7); C049347:fasudil