Early onset of aging phenotype in vascular repair by Mas receptor deficiency

Abstract

Aging is associated with impaired vascular repair following ischemic insult, largely due to reparative dysfunctions of progenitor cells. Activation of Mas receptor (MasR) was shown to reverse aging-associated vasoreparative dysfunction. This study tested the impact of MasR-deficiency on mobilization and vasoreparative functions with aging. Wild type (WT) or MasR-deficient mice (MasR^-/- or MasR^+/-) at 12-14 weeks (young) or middle age (11-12 months) (MA) were used in the study. Mobilization of lineage-negative, Sca-1-positive cKit-positive (LSK) cells in response to G-CSF or plerixafor was determined. Hindlimb ischemia (HLI) was induced by femoral artery ligation. Mobilization and blood flow recovery were monitored post-HLI. Radiation chimeras were made by lethal irradiation of WT or MasR^-/- mice followed by administration of bone marrow cells from MasR^-/- or WT mice, respectively. Nitric oxide (NO) generation by stromal-derived factor-1α (SDF) and mitochondrial reactive oxygen species (mitoROS) levels were determined by flow cytometry. Effect of A779 treatment on mobilization, blood flow recovery, and NO and ROS levels were determined in young WT and MasR^+/- mice. Circulating LSK cells in basal or in response to plerixafor or G-CSF or in response to ischemic injury were lower in MasR^-/- mice compared to the WT. Responses in MasR^+/- mice were similar to the WT at young age but at the middle age, impairments were observed. Impaired mobilization to ischemia or G-CSF was rescued in WT → MasR^-/- chimeras. NO levels were lower and mitoROS were higher in MasR^-/- LSK cells compared to WT cells. A779 precipitated dysfunctions in young-MasR^+/- mice similar to that observed in MA-MasR^+/-, and this accompanied decreased NO generation by SDF and enhanced mitoROS levels. This study shows that mice at MA do not exhibit vasoreparative dysfunction. Either partial or total loss of MasR precipitates advanced-aging phenotype likely due to lack of NO and oxidative stress.

Keywords: Aging; Ischemia; Mas receptor; Vasculogenic progenitor cells.