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Role of BMP signaling in monocyte recruitment and atherosclerotic plaque formation: a study in mouse models and humans


Atherosclerosis (ATS) is a chronic vascular disease and a major cause of death worldwide. Monocytes and macrophages, along with vascular smooth muscle cells (VSMCs), play essential roles in all phases of atherogenesis. Bone morphogenetic proteins (BMPs) have been associated with ATS development, including induction of vascular calcification and inflammation. Preliminary data from our lab demonstrate that the expression of BMP-2 e -4, as well as of Gremlin, a BMP antagonist, is increased in atherosclerotic lesions of apolipoprotein E knockout mice. In addition, primary VSMCs overexpress those genes in early phases of ATS, when plaques are not yet detectable by conventional histology. Furthermore, BMPs and Gremlin modulate VSMC-induced monocyte chemoattraction. However, the mechanisms involved in that phenomenon remain unknown. The present study will pursue this line of investigation. Here we list sets of in vitro and in vivo experiments based on mouse models of ATS. A separate group of studies based on biochemical and histological analyses of samples obtained from patients with peripheral vascular disease is proposed. We seek to better understand mechanisms related to BMP-triggered monocyte chemotaxis. In parallel, by means of various experimental approaches, we will attempt to identify consequences of our findings on ATS pathophysiology. (AU)

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