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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1529.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Bone Marrow Angiotensin AT₁ Receptor Regulates Differentiation of Monocyte Lineage Progenitors From Hematopoietic Stem Cells

Yoshinori Tsubakimoto; Hiroyuki Yamada; Hirokazu Yokoi; Sou Kishida; Hiroki Takata; Hiroyuki Kawahito; Akihiro Matsui; Norifumi Urao; Yoshihisa Nozawa; Hideyo Hirai; Jiro Imanishi; Eishi Ashihara; Taira Maekawa; Tomosaburo Takahashi; Mitsuhiko Okigaki; Hiroaki Matsubara

From the Department of Cardiovascular Medicine (Y.T., H. Yamada, H. Yokoi, S.K., H.T., H.K., A.M., N.U., T.T., M.O., H.M.) and the Department of Microbiology (H.H., J.I.), Kyoto Prefectural University School of Medicine, Japan; Pharmacobioregulation Research Laboratory (Y.N.), Taiho Pharmaceutical Co Ltd, Iinou, Japan; and the Department of Transfusion Medicine and Cell Therapy (E.A., T.M.), Kyoto University Hospital, Japan.

Correspondence to Hiroyuki Yamada, MD, PhD, Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566 Japan. E-mail hiyamada{at}koto.kpu-m.ac.jp

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-Kit⁺Sca-1^–Lin^–CD34⁺CD16/32⁺) and peripheral blood monocytes. Macrophage-colony-stimulating factor (M-CSF)–induced differentiation from hematopoietic stem cells (HSCs:c-Kit⁺Sca-1⁺Lin^–) to promonocytes (CD11b^highLy-6G^low) 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- and JAK2. c-Fms expression in HSCs/promonocytes was mainly regulated by TNF- derived from BM CD45^–CD34^– stromal cells, and Ang II specifically regulated the TNF- 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- to promote M-CSF–induced differentiation/proliferation of monocyte-lineage cells and contributes to the proatherogenic action.

Ang II affects the expression profile of the M-CSF receptor c-Fms through BM stromal cell–derived TNF- and thereby regulates M-CSF–mediated differentiation/proliferation of BM monocyte-lineage cells followed by the mobilization of monocytes, which contribute to the AT₁-mediated proatherogenic actions.

Key Words: bone marrow progenitors • angiotensin • monocyte • atherosclerosis • M-CSF