Bone Marrow Angiotensin AT ₁ Receptor Regulates Differentiation of Monocyte Lineage Progenitors From Hematopoietic Stem Cells

Abstract

Background-The angiotensin II (Ang II) type 1 (AT 1 ) 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 Ϫ/Ϫ mice repopulated with AT 1 -deficient (Agtr1 Key Words: bone marrow progenitors Ⅲ angiotensin Ⅲ monocyte Ⅲ atherosclerosis Ⅲ M-CSF T he angiotensin II (Ang II) type 1 (AT 1 ) receptor exerts proatherogenic actions. 1 AT 1 receptor-deficient (Agtr1 Ϫ/Ϫ ) mice showed a significant reduction of atherosclerotic development, 2,3 and treatment with AT 1 receptor blocker (ARB) reduced the size of atherosclerotic lesions both in experimental animals and humans. 4 AT 1 receptors are present in a variety of cells, including endothelial cells, vascular smooth muscle cells, and bone marrow (BM) stem cells and progenitors. 5,6 Recently, Cassis et al demonstrated that Ang II-induced atherosclerosis was significantly attenuated in LDL receptor-deficient (LDLr Ϫ/Ϫ ) mice whose BM cells were repopulated with Agtr1 Ϫ/Ϫ cells. 7 Fukuda et al also reported that atherosclerotic lesion development was significantly reduced in apoE-deficient (apoE Ϫ/Ϫ ) mice with Agtr1 Ϫ/Ϫ marrow. 8 However, no information regarding the role of the BM-AT 1 receptor on the differentiation/proliferation and properties of BM stem cells and progenitors has been reported in these previous studies.Monocytes and macrophages play a crucial role in the pathogenesis of atherosclerosis, which is characterized by plaque progression, destabilization, and subsequent plaque rupture, through foam cell formation, migration/proliferation of resident vascular smooth muscle cells, and degradation of extracellular matrix. 9 Along with the previous studies showing the effect of diet-induced hypercholesterolemia on BM and leukocyte, 10 Swirski et al reported that hypercholesterolemia induced a surprisingly profound expansion of blood monocytes as well as BM monocyte-lineage cells. 11 However, the relative contribution of the BM renin-angiotensin system to hypercholesterolemia-associated monocytosis has not been fully investigated. 12 In the present study, we focused on the action of the AT 1 receptor expressed in BM cells and studied whether (1) Ang II affects the differentiation/proliferation from BM stem cells into monocyte-lineage cells, and (2) MethodsA full description of all methods can be found in the Data Supplement (available online at http://atvb.ahajournals.org). Animal PreparationApoE Ϫ/Ϫ mice (C57BL/6) and AT1a receptor-deficient (Agtr1 Ϫ/Ϫ ) mice (C57BL/6) were obtained from Taconic Co Ltd (Germantown, NY) and Tanabe Seiyaku Co Ltd (Osaka, Japan), respectively. BM cells of 2-month-old female apoE Ϫ/Ϫ recipient mice were repopulated with male Agtr1 Ϫ/Ϫ or Agtr1 ϩ/ϩ cells. The percentage chimerism determined by transplanting GFP-overexpressing BM cells was 96Ϯ2% of peripheral blood mononuclear cells. 13 Furthermore, BM CD45 Ϫ CD34 Ϫ stromal cells, HSCs, and myeloid ...

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

“…These data suggest that AT1 receptor signaling is required for terminal myeloid differentiation. In studies using AT1 receptor knockout hematopoietic cells, Tsubakimoto et al (2009) also concluded that AT1 signaling was required for normal macrophage development.…”

“…Although blockade of the AT1 receptor slowed myeloid differentiation, macrophage production was ultimately not blocked since, in steady state, both AT1 receptor knockout mice and ACE knockout mice have normal numbers of monocytes and macrophages in the bone marrow and in peripheral blood (Tsubakimoto et al, 2009;Lin et al, 2011). When wild-type bone marrow cultures were treated with losartan, differentiated F4/80 high macrophages developed with normal morphology, but these cells showed functional immaturity, as indicated by decreased tumor necrosis factor a (TNFa) secretion, decreased CD86 upregulation, and a decreased oxidative burst .…”

Everolimus Limits Aortic Aneurysm in the Apolipoprotein E–Deficient Mouse by Downregulating C-C Chemokine Receptor 2 Positive Monocytes

“…35 As the A2-infused ApoE -/-mouse model was used in the current study, we examined the action of A2 on purified ApoE -/-mouse BMM in vitro and demonstrated dose-dependent stimulation of both CCR2 expression and IFNγ production in these cells. The significance of this lies in the fact that IFNγ signaling has been implicated in monocyte activation and recruitment in chronic inflammation.…”

Vascular Wall Progenitor Cells in Health and Disease

“…11 It has been shown that macrophage colony-stimulating factor-induced differentiation of BM HSCs toward monocytes/macrophages is regulated by tumor necrosis factor (TNF)-α released from MSCs, which in turn, is under the influence of angiotensin II. 83 Notably, all three of these soluble factors readily stimulate adventitial macrophage accumulation and induce or aggravate vascular remodeling in atherosclerosis and aneurysm formation. …”