Abstract 020: Angiotensin Ii-induced Hypertension Has Significant Effects On Proliferation, Differentiation And Engraftment Efficacy Of Hematopoietic Stem Cell.

Abstract

Cyclosporin and other immunosuppressive drugs are used in bone marrow (BM) transplantation to increase engraftment efficacy and reduce rejection. However, their chronic clinical use is closely associated with increase in blood pressure and development of hypertension (HTN). Despite these significant side effects, little is known about the influence of high blood pressure on hematopoietic stem cell (HSC) and BM activity. Thus, the objective of this study was to investigate if Ang II induced HTN exerts influence on HSC proliferation, differentiation and engraftment in the BM. Infusion of Ang II (1000ng/kg/min for 21 days) and establishment of HTN resulted in increased proliferation of HSCs as evidenced by 87% increase in Sca-1+, c-Kit+, Lin- (SKL) HSC and 254% increase in CD150+, CD48- SKL long-term HSC in the BM. Furthermore, this was associated with significant accumulation of monocytes in both BM (30% increase) and spleen (250% increase). These changes in HSC and inflammatory cells were blocked by co-infusion of Ang II and losartan (60mg/kg/day), In order to understand the effect of Ang II on HSC homing, GFP+ HSCs were injected into the lethally irradiated and saline or Ang II infused C57BL6 mice. FACS analysis of GFP+ donor derived cells showed that hypertensive animals has poor engraftment efficacy on both BM and peripheral blood (35-52% compared to saline controls). Time-lapse in vivo imaging of mouse tibia showed that HSC failed to engraft to the BM osteoblastic niche in hypertensive mice. HSCs pretreated with 100nM Ang II for 18 hours in vitro also showed significantly diminished ability (16% compared to control) to engraft in normal recipient mice. These observations demonstrate that 1) chronic Ang II induced HTN regulates HSC proliferation and impairs the homing ability and reconstitution potential of HSC in BM, 2) These effects are mediated by the AT1 receptor on HSC and 3) Ang II accelerates HSC differentiation leading the increase of inflammatory cells in BM and spleen. The results suggest that hypertensive status and BP control should be strictly taken into account in consideration for BM transplantation.