Angiotensin II‐induced Hypertension Impairs Hematopoietic Stem Cell Homing and Engraftment

Abstract

Immunosuppressive drugs such as cyclosporine commonly used in hematopoietic stem cell transplantation (HSCT), increase patients' blood pressure. Despite this hypertensive side effect, little is known about the influence of hypertension (HTN) on HSC and bone marrow (BM) activity. The objective of this study was to investigate if HTN exerts deleterious influences on HSC biology and its engraftment compromising efficient transplantation. Ang II induced HTN resulted in increased proliferation of HSCs as evidenced by 83% increase in Sca‐1+, c‐Kit+, Lin‐ (SKL) hematopoietic stem/progenitor cells (HSPC) and 207% increase in CD150+, CD48‐ SKL long‐term HSC (LT‐HSC) in mice. In contrast, hypertensive mice that were lethally irradiated and reconstituted with HSC had 65% diminished engraftment efficacy. The retrospective analysis of HSC transplanted patients showed that graft failure patients tended to have HTN when compared to the well‐recovered group (50% vs. 25%). Time‐lapse in vivo imaging of mouse tibia demonstrated that HSC in HTN mice failed to engraft to the BM osteoblastic HSC niche due to untimely proliferation and differentiation from Ang II infusion. In addition, HSCs pretreated with Ang II for 18 hours in vitro showed diminished BM reconstitution ability showing that Ang II directly modulates the HSC engraftment potential. These observations demonstrate that 1) chronic Ang II‐induced HTN regulates HSC proliferation, 2) although the hypertrophic effect of Ang II increases the HSC numbers, it impairs the homing ability and reconstitution potential of donor HSCs. They suggest that HTN and BP control should be important consideration in clinical application of HSCT.