Abstract
Adult CD34+ hematopoietic stem/progenitor cells (HSPC) in the systemic circulation are bone marrow-derived and have the propensity of maintaining cardiovascular health. Activation of angiotensin-converting enzyme-2 (ACE2)-angiotensin-(1-7)-Mas receptor pathway, the vascular protective axis of the renin-angiotensin system (RAS), stimulates vasculogenic functions of HSPCs. In a previous study, exposure to hypoxia increased the expressions of ACE2 and Mas, and stimulated ACE2 shedding. The current study tested if blood flow restriction exercise (BFR)-induced regional hypoxia recapitulates the in vitro observations in healthy adults. Hypoxia was induced by 80% limb occlusion pressure (LOP) via inflation cuff. Muscle oxygen saturation was determined using near-infrared spectroscopy. Peripheral blood was collected 30 min after quiet sitting (control) or after BFR. Lin-CD45lowCD34+ HSPCs were enumerated by flow cytometry, and ACE and ACE2 activities were determined in plasma and cell lysates and supernatants. Regional hypoxia resulted in muscle oxygen saturation of 17.5% compared with 49.7% in the control condition (P < 0.0001, n = 9). Circulating HSPCs were increased following BFR (834.8 ± 62.1/mL) compared with control (365 ± 59, P < 0.001, n = 7), which was associated with increased stromal-derived factor 1α and vascular endothelial growth factor receptor levels by four- and threefold, respectively (P < 0.001). ACE2 activity was increased in the whole cell lysates of HSPCs, resulting in an ACE2-to-ACE ratio of 11.7 ± 0.5 in BFR vs 9.1 ± 0.9 in control (P < 0.05). Cell supernatants have threefold increase in the ACE2-to-ACE ratio following BFR compared with control (P < 0.001). Collectively, these findings provide strong evidence for the upregulation of ACE2 by acute regional hypoxia in vivo. Hypoxic exercise regimens appear to be promising means of enhancing vascular regenerative capacity.NEW & NOTEWORTHY Although many studies have explored the mechanisms of skeletal muscle growth and adaptation with hypoxia exercise interventions, less attention has been given to the potential for vascular adaptation and regenerative capacity. This study shows for the first time an acute upregulation of the angiotensin-converting enzyme 2 and increase in CD34+ vasculogenic cells following an acute bout of blood flow restriction with low-intensity exercise. These rapid changes collectively promote skeletal muscle angiogenesis. Therefore, this study supports the potential of hypoxic exercise interventions with low intensity for vascular and muscle health.