HL-Regulation of Angiogenesis in the Obese Adipose Tissue by Secreted microRNAs

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PROJECT SUMMARY HL-142: Obesity and its accompanying metabolic disorders represent the great public health challenge of our time and is considered an independent risk factor for cardiovascular disease (CVD). Adipose tissue (AT) expansion and remodeling is an ongoing process that is pathologically altered in the obese state, which is characterized by increased pro-inflammatory state, inadequate angiogenic response and fibrosis. Although adipocytes are key players orchestrating local changes in the microenvironment, much evidence also points towards a pivotal role for macrophages in such remodeling events, by affecting both adipocyte and endothelial cell (EC) angiogenic functions. Because angiogenesis is a rate-limiting step for AT remodeling, it is essential to understand the crosstalk between macrophages and ECs. It is accepted that obesity is accompanied by a change in the composition of macrophages, from an anti-inflammatory and angiogenic form, to a highly inflammatory form responsible for the negative outcomes that arise from obesity. Important players of the post-transcriptional regulatory network are the small non- coding RNAs, microRNAs (miRNAs), which have a demonstrated role in the control of transcriptional networks in MΦs. Intriguingly, miRNAs can be transferred from cell to cell by exosomes, thus facilitating the exchange of information among cells. The molecular composition and content of exosomes may vary depending on whether the secretion is constitutive or a consequence of cell activation. We hypothesize that in obese AT, activated macrophages produce exosomes that contain a specific set of miRNAs that target ECs modulating their function, by controlling gene expression and therefore affecting AT expansion and remodeling. This project will: answer important questions regarding exosome specificity and function; provide critical insights into the contribution of macrophage-derived microRNAs as vehicles of paracrine communication between macrophage and ECs in the regulation angiogenesis in the AT. These findings will pave the way to the identification of innovative therapeutic strategies to modulate AT expansion and remodeling during obesity.