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Reversal of Aging‐Associated Vasoreparative Dysfunction and Myelopoietic Bias in Bone Marrow Stem/Progenitor Cells by Angiotensin‐(1‐7)
Author(s) -
Chittimalli Kishore,
Sakamuri Anil,
Jahan Jesmin,
Joshi Shrinidh,
Jarajapu Yagna
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02354
Subject(s) - bone marrow , progenitor cell , haematopoiesis , angiotensin ii , cd34 , medicine , endocrinology , myeloid , stem cell , immunology , chemistry , biology , microbiology and biotechnology , receptor
Aging increases risk for ischemic vascular diseases. Bone marrow‐derived hematopoietic stem/progenitor cells (HSPCs) are known to stimulate vascular regeneration. However, aging impairs vasoreparative functions and myelopoietic bias in HSPCs. The alternative axis of renin‐angiotensin system, angiotensin converting enzyme‐2 (ACE2)/ angiotensin‐(1‐7) (Ang‐(1‐7)/Mas receptor (MasR), is vasoprotective in contrast to the canonical pathway ACE/Ang II/AT1 receptor. This study tested if MasR activation by Ang‐(1‐7) restores vasoreparative functions in HSPCs derived from aging mice. Lin ‐ Sca‐1 + cKit + (LSK) cells were isolated from Young (3‐5 months) (n=10) or Old (20‐22 months) (n=10) mice, and migration and proliferation were evaluated. Old mice were treated with Ang‐(1‐7) (1 µg/Kg/min, four weeks). Hindlimb ischemia was induced by femoral ligation, and mobilization of LSK cells into the blood circulation was determined. Blood flow recovery was monitored by Laser Doppler blood flow meter and vascular density was evaluated by immunohistochemistry for CD31 and isolectin B4‐positive structures. Myeloid cells in bone marrow were evaluated by colony forming unit (CFU) assay for granulocyte‐macrophage differentiation, followed by flow cytometry of monocyte (Ly6G ‐ CD11b + Ly6C hi ) and macrophage (Ly6G ‐ CD11b + F4/80 + Ly6C hi ) populations. Pro‐myelopoietic factors, S100A8/A9, in the bone marrow supernatant were probed by western blotting. Old mice have decreased number of LSK cells in the circulation with reduced migration or proliferation in response to stromal‐derived factor‐1α, compared to Young (n=6). These dysfunctions were reversed by Ang‐(1‐7). Ischemia increased the number of circulating LSK cells in Young mice and restored blood flow to ischemic areas (n=6). These responses were impaired in Old mice but were restored by treatment with Ang‐(1‐7) (n=6). Neovascularization of ischemic areas is reduced in old mice compared to the Young and was restored by Ang‐(1‐7) (n=4). CFU assay revealed that myelopoiesis is upregulated in the Old bone marrow (increased differentiation into monocyte‐macrophage populations) with increased levels of S100A8/A9, compared to the Young. Treatment of Old mice with Ang‐(1‐7), decreased myelopoietic differentiation and S100A8/A9 concentration to similar levels as in Young (n=4). These results suggest that activation of MasR would be a promising approach for enhancing vasoreparative potential of stem/progenitor cells in aging.