title: Angiotensin II Regulation of Proliferation, Differentiation, and Engraftment of Hematopoietic Stem Cells.
abstract: Emerging evidence indicates that differentiation and mobilization of hematopoietic cell are critical in the development and establishment of hypertension and hypertension-linked vascular pathophysiology. This, coupled with the intimate involvement of the hyperactive renin-angiotensin system in hypertension, led us to investigate the hypothesis that chronic angiotensin II (Ang II) infusion affects hematopoietic stem cell (HSC) regulation at the level of the bone marrow. Ang II infusion resulted in increases in hematopoietic stem/progenitor cells (83%) and long-term HSC (207%) in the bone marrow. Interestingly, increases of HSCs and long-term HSCs were more pronounced in the spleen (228% and 1117%, respectively). Furthermore, we observed higher expression of C-C chemokine receptor type 2 in these HSCs, indicating there was increased myeloid differentiation in Ang II-infused mice. This was associated with accumulation of C-C chemokine receptor type 2(+) proinflammatory monocytes in the spleen. In contrast, decreased engraftment efficiency of GFP(+) HSC was observed after Ang II infusion. Time-lapse in vivo imaging and in vitro Ang II pretreatment demonstrated that Ang II induces untimely proliferation and differentiation of the donor HSC resulting in diminished HSC engraftment and bone marrow reconstitution. We conclude that (1) chronic Ang II infusion regulates HSC proliferation, mediated by angiotensin receptor type 1a, (2) Ang II accelerates HSC to myeloid differentiation resulting in accumulation of C-C chemokine receptor type 2(+) HSCs and inflammatory monocytes in the spleen, and (3) Ang II impairs homing and reconstitution potentials of the donor HSCs. These observations highlight the important regulatory roles of Ang II on HSC proliferation, differentiation, and engraftment.
authors.affiliation: From the Departments of Physiology and Functional Genomics (S.K., M.Z., M.K.R.), Pharmacology and Therapeutics (J.K.H., D.L.), Molecular Genetics and Microbiology (E.W.S.), and Medicine (C.R.C.), College of Medicine, University of Florida, Gainesville.
authors.forename: Seungbum
authors.initials: S
authors.lastname: Kim
authors.affiliation: From the Departments of Physiology and Functional Genomics (S.K., M.Z., M.K.R.), Pharmacology and Therapeutics (J.K.H., D.L.), Molecular Genetics and Microbiology (E.W.S.), and Medicine (C.R.C.), College of Medicine, University of Florida, Gainesville.
authors.forename: Michael
authors.initials: M
authors.lastname: Zingler
authors.affiliation: From the Departments of Physiology and Functional Genomics (S.K., M.Z., M.K.R.), Pharmacology and Therapeutics (J.K.H., D.L.), Molecular Genetics and Microbiology (E.W.S.), and Medicine (C.R.C.), College of Medicine, University of Florida, Gainesville.
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Harrison
authors.affiliation: From the Departments of Physiology and Functional Genomics (S.K., M.Z., M.K.R.), Pharmacology and Therapeutics (J.K.H., D.L.), Molecular Genetics and Microbiology (E.W.S.), and Medicine (C.R.C.), College of Medicine, University of Florida, Gainesville.
authors.forename: Edward W
authors.initials: EW
authors.lastname: Scott
authors.affiliation: From the Departments of Physiology and Functional Genomics (S.K., M.Z., M.K.R.), Pharmacology and Therapeutics (J.K.H., D.L.), Molecular Genetics and Microbiology (E.W.S.), and Medicine (C.R.C.), College of Medicine, University of Florida, Gainesville.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Cogle
authors.affiliation: From the Departments of Physiology and Functional Genomics (S.K., M.Z., M.K.R.), Pharmacology and Therapeutics (J.K.H., D.L.), Molecular Genetics and Microbiology (E.W.S.), and Medicine (C.R.C.), College of Medicine, University of Florida, Gainesville.
authors.forename: Defang
authors.initials: D
authors.lastname: Luo
authors.affiliation: From the Departments of Physiology and Functional Genomics (S.K., M.Z., M.K.R.), Pharmacology and Therapeutics (J.K.H., D.L.), Molecular Genetics and Microbiology (E.W.S.), and Medicine (C.R.C.), College of Medicine, University of Florida, Gainesville. mraizada@ufl.edu.
authors.forename: Mohan K
authors.initials: MK
authors.lastname: Raizada
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006973:Hypertension / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D014741:Video Recording
chemical_list: D000804:Angiotensin II
keywords: angiotensin II; bone marrow transplantation; hematopoietic stem cells; hypertension; inflammation