INTRODUCTION: Emerging evidence indicates that differentiation and mobilization of hematopoietic stem cell (HSC) are critical in the development and establishment of hypertension-linked vascular pathophysiology. This, coupled with the intimate involvement of a hyperactive renin-angiontensin system in hypertension, led us to propose the hypothesis that chronic angiotensin II (Ang II) infusion would regulate HSC proliferation and differentiation at the bone marrow level.
METHODS: 1) Ang II was chronically infused into C57BL6 mice using mini-osmotic pumps (1500ng/kg/min) for 3 weeks. This resulted in an increase in MAP of 45mmHg. Bone marrow, peripheral blood and splenocytes from control and Ang II-treated mice were analyzed using FACS. 2) 0.5-3 X104 GFP+ Sca-1+, c-Kit+, Lin- (SKL) HSC were pre-incubated with Ang II for 24h in vitro (100μg/ml), rinsed and injected into lethally irradiated C57BL6 mice. Donor derived GFP+ cells were analyzed by FACS and histology to evaluate engraftment efficiency.
RESULTS: We observed a 32% decrease of HSCs in the bone marrow of Ang II treated mice. In addition, there was an 29-52% increase in the number of CX3CR1+/Gr-1- monocyte in the peripheral blood and spleen. These changes in HSC and myeloid cells were blocked by co-treatment of Losartan (60mg/kg/day, ip injection). Next, we investigated if Ang II affects HSC homing and engraftment efficacy, which are critical steps in successful bone marrow transplantation. We observed a significant delay of the homing GFP+ SKL cells that were pre-treated with Ang II in lethally irradiated recipient mice. In addition, the SKL cells treated with Ang II failed to efficiently engraft to the innate osteoblastic niche. Consistent with this observation, colony formation unit-Spleen (CFU-S) in the Ang II infused recipients was reduced to 65% compared to control mice.
CONCLUSION: These observations demonstrate that hypertension induced by chronic Ang II infusion significantly impairs the engraftment ability of HSC in the bone marrow, which appears to be mediated by the AT1R on HSC and that Ang II accelerates HSC differentiation into myeloid lineage. These multifaceted roles of Ang II indicate that Ang II acts as an important regulator of HSC in the bone marrow.