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Role of the BMP signaling pathway in the recruitment of cells from the immune system in the progression of atherosclerosis.

Abstract

The development of atherosclerosis involves the activation/modification of several cell types, including endothelial, vascular smooth muscle (VSMC) and immune cells, such as monocytes, macrophages, dendritic cells and T lymphocytes. In a previous study, we demonstrated that BMPs (-2 and -4), as well as the BMP antagonist Gremlin, are supra-regulated in aortas and in VSMC from animals prone to atherosclerosis fed with a hyperlipidemic diet. We also documented the causative role of BMPs in the induction of migration and infiltration of monocytes to the vascular wall, favoring local inflammation and consequent formation of atheroma plaques. Knowing this crucial function of BMPs in atherosclerosis, we established a line of mice through the crossbreeding of Apolipoprotein E deficient (ApoE-/-) and Gremlin haploinsufficient (Grem+/-) animals, thus creating a model of gain of BMP function (Grem+/- ApoE-/-). It is noteworthy that after 8 weeks of hyperlipidemic diet, those animals showed lower counts of monocytes (CD11b +) and dendritic cells (CD11c+ CD11b+) in the aortas, when compared to ApoE-/- animals fed with the same diet. We also documented histological consequences of those findings, with lower volumes of atherosclerotic plaques in Grem+/- ApoE-/- mice when compared to ApoE-/- animals under the same conditions. Our data indicates Grem+/- ApoE-/- animas are interesting tools for the study of the role of immune cells in atherogenesis. Our initial data open a range of possibilities for seeking a better understanding of the relationship between vascular and extravascular elements, cells of the immune system and BMP signaling in atherosclerosis. Thus, in this new study we propose to evaluate the mechanisms of BPMs signaling pathway and the immune cells involvement on the origin and progression of the atherogenesis. Results from this project may lead to additional knowledge in the field of cardiovascular pathophysiology in general and atherogenesis in particular. (AU)

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