ACE2/ACE imbalance and impaired vasoreparative functions of stem/progenitor cells in aging

Abstract

Aging increases risk for ischemic vascular diseases. Bone marrow-derived hematopoietic stem/ progenitor cells (HSPCs) are known to stimulate vascular regeneration. Activation of either the Mas receptor (MasR) by angiotensin-(1-7) (Ang-(1-7)) or angiotensinconverting enzyme-2 (ACE2) stimulates vasoreparative functions in HSPCs. This study tested if aging is associated with decreased ACE2 expression in HSPCs and if Ang-(1-7) restores vasoreparative functions. Flow cytometric enumeration of Lin − CD45 low CD34 + cells was carried out in peripheral blood of male or female individuals (22-83 years of age). Activity of ACE2 or the classical angiotensin-converting enzyme (ACE) was determined in lysates of HSPCs. Lin − Sca-1 + cKit + (LSK) cells were isolated from young (3-5 months) or old (20-22 months) mice, and migration and proliferation were evaluated. Old mice were treated with Ang-(1-7), and mobilization of HSPCs was determined following ischemia induced by femoral ligation. A laser Doppler blood flow meter was used to determine blood flow. Aging was associated with decreased number (Spearman r = − 0.598, P < 0.0001, n = 56), decreased ACE2 (r = − 0.677, P < 0.0004), and increased ACE activity (r = 0.872, P < 0.0001) (n = 23) in HSPCs. Migration or proliferation of LSK cells in basal or in response to stromal-derived factor-1α in old cells is attenuated compared to young, and these dysfunctions were reversed by Ang-(1-7). Ischemia increased the number of circulating LSK cells in young mice, and blood flow to ischemic areas was recovered. These responses were impaired in old mice but were restored by treatment with Ang-(1-7). These results suggest that activation of ACE2 or MasR would be a promising approach for enhancing ischemic vascular repair in aging.

Paracrine-mediated rejuvenation of aged mesenchymal stem cells is associated with downregulation of the autophagy-lysosomal pathway

“…Furthermore, results of studies in immunosuppressed rats post-MI demonstrated that intramyocardial injection of human MSCs from old donors is less effective than those from young donors as assessed by left ventricular ejection fraction, fractional shortening, and left ventricular cavity dimensions 2 . Similarly, bone marrow-derived hematopoietic stem/progenitor cells (HSCPCs) derived from aged mice show impaired vascular repair potential compared to those isolated from young mice, a difference that correlates with lower expression of ACE2 in the aged HSCPCs 27 .…”

SARS-CoV-2 interacts with renin-angiotensin system: impact on the central nervous system in elderly patients

“…In the bloodstream, the level of soluble ACE2 is normally lower than 17 mU/L [117,118] but becomes elevated in different cardiovascular disorders [117][118][119][120]. Probably promoted by the SARS-CoV-2 infection, it is also raised among patients with severe COVID-19 [121], which could be more pronounced among older patients [86,119,[122][123][124]. However, contradictory results have been reported regarding circulating ACE2 activity in SARS-CoV-2 infected patients that is ranging from elevated [125][126][127][128][129][130][131] to unchanged [132,133] or even lowered circulating ACE2 levels [134].…”

Metabolism in the Midwest: research from the Midwest Aging Consortium at the 49th Annual Meeting of the American Aging Association

“…Biological aging is traditionally thought of as the progressive loss of functional characteristics on a cellular and organismal level. Both impaired stem cell function and accumulated senescent cells contribute to this process [23][24][25][26]. Cells that reach the point of irreversible cell arrest are considered to be senescent.…”