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  • Epidermal Growth Factor (EGF), human recombinant receptor Ab


    Abdominal aortic aneurysm (AAA) is considered a major health concern and is associated with extremely high rates of mortality in case of aortic rupture. The main pathophysiologic mechanisms leading to aortic dilation include the degradation of the extracellular matrix (ECM) components, such as collagen and elastin fibers; the impairment of vascular smooth muscle cell (VSMC) homeostasis; and the infiltration of inflammatory cells in the media and the intima. Even if the main features leading to aortic wall weakness and rupture have been identified, no pharmacologic treatment is currently available to prevent or to limit AAA development, underlining the real need to develop clinical and fundamental research. To explore cellular and molecular pathways involved in AAA development, several experimental models of aneurysms have been developed during the past decades., Among them, chemically induced aneurysms are the most commonly used and are classically divided into two categories. Dissecting AAA models usually induce a medial dissection, leading to intramural hemorrhage and secondary rupture. Even if dissecting AAA models reproduce the main pathophysiologic features of human disease, including ECM degradation and inflammatory cell infiltration, medial dissection is not frequently observed in human AAA. Nondissecting AAA animal models, generated mainly through application of elastase or calcium chloride on the aortic wall, lead to ECM alteration, inflammation, and dilation of the Epidermal Growth Factor (EGF), human recombinant receptor but do not induce aortic rupture. We recently showed that systemic blockade of transforming growth factor β (TGF-β) activity in a nondissecting elastase-induced AAA model sustained aneurysmal growth, led to aortic rupture, and reproduced the main characteristics of human disease, such as ECM degradation, intraluminal thrombus formation, and leukocyte infiltration including T cells, neutrophils, and macrophages. Elastase application is mandatory to initiate the aortic dilation as TGF-β neutralization alone does not induce vascular disease. Depletion of macrophages in this model led to a complete inhibition of AAA rupture. During the past decades, several studies addressed the role of macrophages during AAA development and revealed interesting potential applications for clinical practice as biomarkers and potential therapeutic targets. In vitro, two main macrophage phenotypes can be distinguished: lipopolysaccharide-induced M1 macrophages, characterized by the expression of proinflammatory proteins such as CCL2, CCL5, NOS2, interleukin (IL) 6, and IL-1β; and IL-4-induced M2 macrophages, characterized by the expression of prohealing proteins, such as FIZZ1, MGL2, arginase 1 (ARG1), Ym1/2, TGF-β, and IL-10. In vivo, the distinction between M1 and M2 macrophages is not clear-cut as markers that distinguish them are not specific and stimuli that activate each subset can be coexpressed within aortic tissue., , It has been suggested that macrophage subsets in aneurysmal tissue rather correspond to a spectrum of activation characterized by a combination of markers that play differential roles in the initiation, progression, and healing of AAA., Whereas the role of several cytokines highly produced by macrophages, such as IL-6, IL-1β, IL-10, and TGF-β, has been well investigated in mouse models of aortic aneurysm,, , , the role of other proteins, such as ARG1, has been poorly investigated. ARG1 catalyzes the final step in the urea cycle, converting arginine into urea and ornithine, and several studies have supported its role in would healing and tissue remodeling. An association between ARG1 expression in macrophages and atherosclerosis resistance was found, suggesting its potential role in cardiovascular diseases. However, its expression in AAA is still poorly known. The aim of our study was to investigate whether macrophages contribute to the expression of canonical M1/M2 markers in the aorta in the AAA model induced by elastase and systemic blockade of TGF-β and whether blocking of TGF-β activity has an impact on macrophage phenotype and ARG1 expression in vivo.