Abstract 1742: Bone Marrow Angiotensin AT1 Receptor Regulates Differentiation of Monocyte/Macrophage-Lineage Progenitors from Hematopoietic Stem Cells
The angiotensin II (Ang II) type 1 (AT1) receptor is expressed on bone marrow (BM) stem cells, whereas it remains poorly defined how BM-AT1 affects on differentiation/proliferation of monocyte progenitors to cause pro-atherogenic actions. We generated BM chimera apoE-deficient (apoE−/−) mice whose BM cells were repopulated with AT1-deficient (Agtr1−/−) or wild type (Agtr1+/+) cells. Four months after BM transplantation, all mice were fed a western diet for further two months. Atherosclerotic lesion area was significantly reduced in apoE−/−/BM-Agtr1−/− mice compared with apoE−/−/BM-Agtr1+/+ mice (31%, P < 0.05), accompanied by the decreased numbers of BM granulocyte/macrophage progenitor cells (GMP) and peripheral blood monocytes (34% and 53%, respectively, P < 0.05). To further investigate the BM-AT1-mediated action on BM stem cells, hematopoietic stem cells (c-Kit+ Sca-1+ lin−, HSCs) were selectively isolated from Agtr1−/− or Agtr1+/+ BM cells. M-CSF induced differentiation to myeloid progenitors (c-Kit+ Sca-1−lin−, MP) and promonocyte (CD11bhighLy-6Glow) was markedly reduced in Agtr1−/− HSCs compared with Agtr1−/− HSCs (40%, P < 0.01). Interestingly, the expression of M-CSF receptor, c-Fms was suppressed in Agtr1−/− HSCs as well as MP and promonocyte (39%, 57%, and 60%, respectively, P < 0.05), accompanied by the marked reduction in M-CSF-induced phosphorylation of PKC-δ and JAK2 (80% and 75%, respectively, P < 0.05). Treatment with AT1 receptor blocker (ARB) reduced the atherosclerotic lesion in apoE−/− mice (65%, P < 0.01), concomitant with a decrease in GMP numbers (50%, P < 0.05) and frequency of circulating Ly-6Chigh monocyte (34%, P < 0.01). ARB treatment also suppressed the macrophage-colony-forming activity of Agtr1−/−BM cells in a dose-dependent manner, but did not affect M-CSF-induced differentiation at the single-cell level. Our findings demonstrate for the first time that BM-AT1 regulates the expression of M-CSF receptor c-Fms on HSCs to promote M-CSF-induced differentiation/proliferation of BM monocyte-macrophage lineage cells, contributing to AT1-mediated proatherogenic action via hypercholesterolemia-associated mobilization of monocytes.