Bone marrow angiotensin AT1 receptor regulates differentiation of monocyte lineage progenitors from hematopoietic stem cells

BACKGROUND-: The angiotensin II (Ang II) type 1 (AT1) receptor is expressed in bone marrow (BM) cells, whereas it remains poorly defined how Ang II regulates differentiation/proliferation of monocyte-lineage cells to exert proatherogenic actions. METHODS AND RESULTS-: We generated BM chimeric apoE mice repopulated with AT1-deficient (Agtr1) or wild-type (Agtr1) BM cells. The atherosclerotic development was significantly reduced in apoE/BM-Agtr1 mice compared with apoE/BM-Agtr1 mice, accompanied by decreased numbers of BM granulocyte/macrophage progenitors (GMP:c-KitSca-1LinCD34CD16/32) and peripheral blood monocytes. Macrophage-colony-stimulating factor (M-CSF)-induced differentiation from hematopoietic stem cells (HSCs:c-KitSca-1Lin) to promonocytes (CD11bLy-6G) was markedly reduced in HSCs from Agtr1 mice. The expression of M-CSF receptor c-Fms was decreased in HSCs/promonocytes from Agtr1 mice, accompanied by a marked inhibition in M-CSF-induced phosphorylation of PKC-δ and JAK2. c-Fms expression in HSCs/promonocytes was mainly regulated by TNF-α derived from BM CD45CD34 stromal cells, and Ang II specifically regulated the TNF-α synthesis and release from BM stromal cells. CONCLUSIONS-: Ang II regulates the expression of c-Fms in HSCs and monocyte-lineage cells through BM stromal cell-derived TNF-α to promote M-CSF-induced differentiation/proliferation of monocyte-lineage cells and contributes to the proatherogenic action.