Vasculopathy-associated hyperangiotensinemia mobilizes haematopoietic stem cells/progenitors through endothelial AT₂R and cytoskeletal dysregulation

Nat Commun. 2015 Jan 9;6:5914. doi: 10.1038/ncomms6914.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Actins / metabolism
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Anemia, Sickle Cell / metabolism
  • Angiotensin II / metabolism*
  • Animals
  • Bone Marrow Cells / cytology
  • Cell Adhesion
  • Cell Membrane / metabolism
  • Crosses, Genetic
  • Cytoskeleton / metabolism*
  • Endothelial Cells / cytology
  • Hematopoiesis
  • Hematopoietic Stem Cells / cytology*
  • Humans
  • Integrin beta1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Confocal
  • Nitric Oxide / chemistry
  • Signal Transduction
  • Stem Cells / cytology*
  • Vascular Diseases / pathology*

Substances

  • Actins
  • Adaptor Proteins, Signal Transducing
  • Agtrap protein, mouse
  • Integrin beta1
  • Angiotensin II
  • Nitric Oxide