title: Vasculopathy-associated hyperangiotensinemia mobilizes haematopoietic stem cells/progenitors through endothelial AT₂R and cytoskeletal dysregulation.
abstract: Patients with organ failure of vascular origin have increased circulating haematopoietic stem cells and progenitors (HSC/P). Plasma levels of angiotensin II (Ang-II), are commonly increased in vasculopathies. Hyperangiotensinemia results in activation of a very distinct Ang-II receptor set, Rho family GTPase members, and actin in bone marrow endothelial cells (BMEC) and HSC/P, which results in decreased membrane integrin activation in both BMEC and HSC/P, and in HSC/P de-adhesion and mobilization. The Ang-II effect can be reversed pharmacologically and genetically by inhibiting Ang-II production or signalling through BMEC AT2R, HSCP Ang-II receptor type 1 (AT1R)/AT2R or HSC/P RhoA, but not by interfering with other vascular tone mediators. Hyperangiotensinemia and high counts of circulating HSC/P seen in sickle cell disease (SCD) as a result of vascular damage, is significantly decreased by Ang-II inhibitors. Our data define for the first time the role of Ang-II HSC/P traffic regulation and redefine the haematopoietic consequences of anti-angiotensin therapy in SCD.
authors.affiliation: 1] Hoxworth Blood Center, University of Cincinnati College of Medicine, 3130 Highland Avenue, Cincinnati, Ohio 45267, USA [2] Division of Experimental Hematology and Cell Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Chang
authors.affiliation: Division of Experimental Hematology and Cell Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Ramesh C
authors.initials: RC
authors.lastname: Nayak
authors.affiliation: Division of Experimental Hematology and Cell Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Swarnava
authors.initials: S
authors.lastname: Roy
authors.affiliation: Hoxworth Blood Center, University of Cincinnati College of Medicine, 3130 Highland Avenue, Cincinnati, Ohio 45267, USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Perumbeti
authors.affiliation: Division of Experimental Hematology and Cell Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Wellendorf
authors.affiliation: Division of Experimental Hematology and Cell Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Katie Y
authors.initials: KY
authors.lastname: Bezold
authors.affiliation: Hoxworth Blood Center, University of Cincinnati College of Medicine, 3130 Highland Avenue, Cincinnati, Ohio 45267, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Pirman
authors.affiliation: Hoxworth Blood Center, University of Cincinnati College of Medicine, 3130 Highland Avenue, Cincinnati, Ohio 45267, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Hill
authors.affiliation: Division of Experimental Hematology and Cell Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Starnes
authors.affiliation: Division of Experimental Hematology and Cell Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Anastacia
authors.initials: A
authors.lastname: Loberg
authors.affiliation: Division of Experimental Hematology and Cell Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, 1161 21st Avenue South, Nashville, Tennessee 37232, USA.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Inagami
authors.affiliation: Division of Experimental Hematology and Cell Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Division of Experimental Hematology and Cell Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Punam
authors.initials: P
authors.lastname: Malik
authors.affiliation: 1] Hoxworth Blood Center, University of Cincinnati College of Medicine, 3130 Highland Avenue, Cincinnati, Ohio 45267, USA [2] Division of Experimental Hematology and Cell Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Cancelas
mesh_terms: D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000755:Anemia, Sickle Cell / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002448:Cell Adhesion; D002462:Cell Membrane / Q000378:metabolism; D003433:Crosses, Genetic; D003599:Cytoskeleton / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009569:Nitric Oxide / Q000737:chemistry; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D014652:Vascular Diseases / Q000473:pathology*
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; C119712:Agtrap protein, mouse; D019012:Integrin beta1; D000804:Angiotensin II; D009569:Nitric Oxide