Angiotensin II Mobilizes Spleen Monocytes to Promote the Development of Abdominal Aortic Aneurysm in Apoe ^−/− Mice

Abstract

Objective-Abdominal aortic aneurysm (AAA) is widespread among elderly people and results in progressive expansion and rupture of the aorta with high mortality. Macrophages, which are the main population observed within the site of aneurysm, are thought to derive from circulating monocytes although no direct evidence has been provided to date. In this study, we were particularly interested in understanding the trafficking behavior of monocyte subsets in AAA and their role in disease pathogenesis. Approach and Results-Using bone marrow transplantation in Apoe−/− mice, we showed that circulating monocytes give rise to abdominal aortic macrophages in hypercholesterolemic mice submitted to angiotensin II (AngII). Detailed monitoring of monocyte compartmentalization revealed that lymphocyte antigen 6C high and lymphocyte antigen 6C low monocytes transiently increase in blood early after AngII infusion and differentially infiltrate the abdominal aorta. The splenic reservoir accounted for the mobilization of the 2 monocyte subsets after 3 days of AngII infusion. Spleen removal or lymphocyte deficiency in Apoe −/− Rag2 −/− mice similarly impaired early monocyte increase in blood in response to AngII and protected against AAA development, independently of blood pressure. Reconstitution of Apoe −/− Rag2 −/− mice with total splenocytes but not with B-cell-depleted splenocytes restored monocyte mobilization in response to AngII and enhanced susceptibility to AAA. Conclusions-Taken together, the data show that lymphocyte antigen 6C high and lymphocyte antigen 6C low monocytes are mobilized from the spleen in response to AngII. Intriguingly, the process is dependent on the presence of B cells and significantly contributes to the development of AAA and the occurrence of aortic rupture. Mellak et al Role of Monocytes in Abdominal Aortic Aneurysm 379lymphocyte antigen 6C (Ly-6C) high monocytes rapidly infiltrate injured tissues and drive chronic inflammation in a CCR2-dependent manner. 18,19 On the other hand, nonclassical (resident) Ly-6C low monocytes express high levels of CX3CR1 and low levels of CCR2, patrol the endothelium of blood vessels, populate normal or inflammatory sites, and may contribute to wound healing. 15,[20][21][22][23][24][25] However, in atherosclerosis, Ly-6C high and Ly-6C low monocytes are continuously recruited to the plaque using distinct chemokine receptor axes, 26-28 even though Ly-6C high monocyte infiltration dominates over Ly-6C low counterparts and gives rise to a large amount of plaque macrophages. 29Blockade of monocyte recruitment has been shown to promote plaque regression. 30Selective mobilization and trafficking patterns of the 2 monocyte subsets could depend on initial inflammatory triggers. For instance, Ly-6C high and Ly-6C low monocytes are sequentially recruited to the heart, soon after myocardial infarction. Although monocytes are mainly mobilized from the bone marrow (BM), recent studies have shed light on alternative mechanisms by which monocytes are rapidly deployed from the splee...

Subcutaneous Angiotensin II Infusion using Osmotic Pumps Induces Aortic Aneurysms in Mice

“…Many recent studies have also demonstrated that AngII induces AAAs in normolipidemic mice [5][6][7] . The approach of infusing AngII has been applied to induce AAAs and explore molecular mechanisms as well as development of potential therapeutic strategies (e.g., [5][6][7][8][9][10][11][12][13][14][15] ) since this model recapitulates many features observed in human AAAs. For example, risk factors of human AAAs such as smoking, aging, and male gender also augment AngII-induced AAAs in mice 16,17 .…”

α7 Nicotinic Acetylcholine Receptor Relieves Angiotensin II–Induced Senescence in Vascular Smooth Muscle Cells by Raising Nicotinamide Adenine Dinucleotide–Dependent SIRT1 Activity

“…Ang II concentration increases with aging in nonhuman primates. 6 Moreover, Ang II mediates the age-dependent cardiomyopathy, 7 mimics age-associated carotid arterial remodeling, 8 promotes abdominal aortic aneurysms, 9,10 and triggers agerelated contractile dysfunction. 11 In addition, inhibition of the Ang II type 1 receptor promotes longevity in mice.…”

Cytokine amplification and macrophage effector functions in aortic inflammation and abdominal aortic aneurysm formation

“…The function of the spleen is important because this organ serves as a reservoir of CD11b + Ly6C hi inflammatory monocytes. Interestingly, splenectomy partially protects from Ang II-induced AAA formation, probably through this mechanism (41). Data from Ang II infusion in IL-6-/-and KLF6-/-mice demonstrate that both IL-6 and GM-CSF are necessary for the full manifestation of aortic pathology as these cytokines amplify aortic cytokine production and promote leukocyte recruitment and maturation.…”