Patients in organ failure of vascular origin have increased circulating hematopoietic 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 signaling through BMEC AT2R, HSCP 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 hematopoietic consequences
of anti-angiotensin therapy in SCD.