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. Increased levels of haematopoietic stem and progenitor cells in the blood have been linked to some forms of organ failure. Here, the authors show that the hormone angiotensin II increases mobilization of haematopoietic stem and progenitor cells by inducing cytoskeletal changes in bone marrow cells.