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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 ...

Patients who underwent PAA showed a higher rate of wound healing and shorter time to wound healing, especially in the moderate-risk population. With regard to wound healing, this aggressive strategy might become a salvage procedure for patients with critical limb ischemia presenting with pedal artery disease.