Abstract
French Extracellular vesicles released by tumors (tEVs) disseminate via circulatory networks and promote microenvironmental changes in distant organs favoring metastatic seeding. Despite their abundance in the bloodstream, how hemodynamics affect the function of circulating tEVs remains unsolved. We demonstrated that efficient uptake of tEVs occurs in venous endothelial cells that are subjected to hemodynamics. Low flow regimes observed in veins partially reroute internalized tEVs toward non-acidic and non-degradative Rab14-positive endosomes, at the expense of lysosomes, suggesting that endothelial mechanosensing diverts tEVs from degradation. Subsequently, tEVs promote the expression of pro-angiogenic transcription factors in low flow-stimulated endothelial cells and favor vessel sprouting in zebrafish. Altogether, we demonstrate that low flow regimes potentiate the pro-tumoral function of circulating tEVs by promoting their uptake and rerouting their trafficking. We propose that tEVs contribute to pre-metastatic niche formation by exploiting endothelial mechanosensing in specific vascular regions with permissive hemodynamics. Under low blood flow conditions, extracellular vesicles released by tumors are mostly internalized by veinous endothelial cells, where they potentiate angiogenesis.Extracellular vesicles released by wtumors are mostly internalized in veinous endothelial cells.Under low blood flow conditions, internalized extracellular vesicles are partially redirected toward non‐degradative compartments.Extracellular vesicles released by tumors stimulate a pro‐angiogenic response in endothelial cells facing low blood flow.