Extracellular vesicle-mediated transfer of cortisol-induced miR-143-3p from macrophages promotes angiogenesis

Chronic stress can lead to hormonal imbalance and contribute to cancer risk and progression. We previously reported higher levels of serum cortisol in breast cancer (BC) patients compared to those without a cancer diagnosis. Furthermore, we observed relatively higher levels of serum cortisol in Black patients than their White counterparts. Additionally, we found that cortisol treatment promoted M2 polarization of macrophages by inducing the expression of miR-143-3p, which was also released in extracellular vesicles (EV). Here, we investigated the role of EV-encapsulated miR-143-3p in angiogenesis, considering the fact that Black patients exhibit a higher microvessel density in their breast tumors. Treatment of endothelial cells with EV from cortisol-treated macrophages (Corti-Mφ-EV) increased their proliferation, migration, invasion, and tube formation. Efficient uptake of EV by endothelial cells was confirmed by fluorescence-based imaging, which correlated with an increase in the intracellular levels of miR-143-3p in Corti-Mφ-EV treated endothelial cells. Pre-treatment of endothelial cells with a miR-143-3p inhibitor abrogated Corti-Mφ-EV-induced proliferation and tube formation, whereas transfection with a miR-143-3p mimic promoted these effects. Computational analysis using the web-based platforms (Targetscan and miRDB) identified IGFBP5 as a potential miR-143-3p target. A reduction in IGFBP5 expression was reported in Corti-Mφ-EV or miR-143-3p mimic-treated endothelial cells. siRNA-mediated knockdown of IGFBP5 also increased endothelial cell growth and tube formation. Interestingly, surveying of the TCGA dataset showed a significant positive correlation between the M2 macrophage marker (CD163) and endothelial cell markers (PECAM1 and CDH5). Altogether, these findings reveal a novel mechanism by which cortisol may promote angiogenesis, establishing an additional pathobiological connection of chronic stress with increased cancer risk.