Abstract 3: Angiotensin II Affects Hematopoietic Stem/progenitor Cell Engraftment and Mobilization

Abstract

Evidence indicates that Angiotensin II (Ang II) induces proliferation of the hematopoietic stem/progenitor cells (HSPCs). However, the mechanism of its action in vivo at the level of bone marrow (BM) remains poorly understood. In the present study, we have used an innovative in vivo imaging technique to visualize mouse tibia bone so that we can elucidate the effect of Ang II on HSPC in the BM. Sca-1+, c-Kit+, Lin- (SKL) HSPCs from GFP mice were isolated and 6-10X10^3 SKL cells were injected into the lethally irradiated C57BL6 mice. SKL cells engrafted in the tibia bone were visualized in real time with the use of tibia window technique. The effect of Ang II on GFP+ SKL cells was studied by chronic infusion of Ang II osmotic minipumps (1000ng/kg/min). We observed a significant delay in the homing of GFP+ SKL cells by Ang II infusion for 7 days. In addition, the SKL cells failed to efficiently engraft to the osteoblastic niche. Consistent with this observation, colony formation unit-Spleen (CFU-S) analysis showed that extramedullary hematopoiesis was drastically reduced in Ang II treated mice. Furthermore, CX3CR1+/Gr-1+ inflammatory monocytes in the peripheral blood were increased by 47% following 2 weeks of Ang II infusion. This was associated with the significant increase of Sca-1+ CX3CR1+ cells in the BM indicating that Ang II also affects monocyte progenitor cells in the BM. Finally, we observed an increased number of BM derived monocytes in the paraventricular nucleus (PVN) of the hypothalamus in Ang II treated mice. These data demonstrate that chronic Ang II infusion inhibits homing of HSPC, prevents their engraftment into the functional BM niche and increases mobilization of monocyte progenitors into the PVN. They suggest that monocyte progenitors derived from the BM may contribute to an increase in the number of activated microglia in the PVN of hypertensive animals.