Blood Flow Restriction Exercise Increases the ACE2/ACE Ratio and ACE2 Shedding in CD34+ Cells in Healthy Individuals

Abstract

Adult CD34+ hematopoietic stem/progenitor cells in the systemic circulation are bone marrow‐derived and have the propensity of maintaining cardiovascular health. We have previously shown that activation of the vascular protective axis of renin angiotensin system (RAS), Angiotensin Converting enzyme‐2 (ACE2)/Angiotensin‐(1–7)/Mas receptor axis stimulates vasoreparative functions of CD34+ cells in health and disease. Importantly, in vitro exposure of CD34+ cells to hypoxia enhanced the expressions of ACE2 and Mas, and stimulated ACE2 shedding, but ACE and AT1 receptors, members of the vascular detrimental axis of RAS were not affected. This study tested if acute regional hypoxia recapitulates the in vitro observations in healthy individuals. Blood flow restriction exercise (BFR) was performed in the lower body by applying 80% limb occlusion pressure (LOP). Delphi personalized tourniquet system was used to accomplish the target LOP. Exercise protocol consisted of total four sets (30/15/15/15 repetitions) of movements at 10% of maximal strength. Muscle oxygen saturation was determined by using MOXY muscle oxygen monitor. Peripheral blood was collected two weeks before (control) and 30 min after BFR. CD34+ cells were enumerated by flow cytometry, and ACE and ACE2 activities in plasma, and in cell lysates and cell‐free supernatants were determined. Plasma concentrations of SDF and VEGF were analyzed by ELISA. BFR prescribed at 80% LOP resulted in muscle oxygen levels of 14.1% compared to 50.9% in the resting condition. As predicted, circulating CD34+ cells were increased following BFR (before 356±59.1 and after 835±62.1/mL blood, P<0.001, n=5), which was associated with increased plasma levels of SDF and VEGF (4‐ and 3‐fold, respectively, compared to control (P<0.001, n=5)). ACE2 activity was increased in the whole cell lysates of Lineage‐negative cells resulting in the ACE2/ACE ratio of 11.7±0.5 compared to the baseline ratio of 9.1±0.9 (P<0.05, n=5). Cell supernatants have 3‐fold increase in ACE2/ACE ratio following BFR compared to the baseline levels (P<0.001, n=5). Collectively, these findings provide compelling evidence for the upregulation of ACE2, the vasoprotective enzyme of RAS, by acute regional hypoxia in HSPCs. BFR‐exercise regimen could be a promising approach for enhancing or restoring cardiovascular health in individuals that are poor mobilizers or those at risk for the development of cardiovascular complications.Support or Funding InformationNational Institute of General Medical Sciences (NIGMS) and National Institute of Aging (NIA) AG056881.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.