Effect of angiotensin II on hematopoietic progenitor cell proliferation.

Angiotensin II (AII) induced the proliferation of hematopoietic progenitor cells (HPC) isolated from murine bone marrow or human cord blood. The formation of colonies with more than 50 cells increased approximately five-sevenfold in cultures of murine lineage-negative (Lin(-)) bone marrow cells both in the presence (day 10) and absence (day 13) of colony-stimulating factors (CSF). This could be blocked with addition of Losartan, an antagonist of AIITR1. The increase in proliferation of early hematopoietic progenitors (Lin(-)Sca l(+) cells) by AII was approximately threefold and occurred only in the presence of CSF, suggesting that AII may affect mesenchymal stromal cells to induce CSF production and might directly affect early HPC. These in vitro studies were replicated with human HPC isolated from cord blood. AII also accelerated the proliferation and formation of colony-forming units (CFU)-granulocyte/erythroid/macrophage/megakaryocyte and CFU-granulocyte/macrophage colonies by CD34(+)CD38(-) enriched progenitors but only in the presence of CSF. Additional studies also indicated that AII can act to increase proliferation in suspension culture. Exposure of CD34(+) cells to AII in suspension culture, prior to placement in a semisolid medium with erythropoietin, increased the formation of colonies with more than 50 cells and erythroid progenitors approximately five- and 20-fold, respectively. Further, mRNA for the AT1a receptor was expressed by human bone marrow CD34(+)CD38(-) cells, CD34(+)CD38(-) cells, and lymphocytes, but not mature myeloid cells. Similarly, mRNA for the AT1a receptor was expressed on human stromal cell clones, offering further support to the hypothesis that AII acts partially through the mesenchymal compartment of the bone marrow. These data suggest that AII may be a factor which stimulates the proliferation of hematopoietic progenitors.