Blood flow diverts extracellular vesicles from endothelial degradative compartments to promote angiogenesis

Abstract

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 experimentally tuned flow profiles in vitro (microfluidics) and in vivo (zebrafish) and demonstrated that efficient uptake of tEVs occurs in endothelial cells subjected to capillary-like hemodynamics. Such flow profiles partially reroute internalized tEVs towards 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 flow-stimulated endothelial cells and favor vessel sprouting in zebrafish. Altogether, we demonstrate that capillary-like flow profiles 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.

Molecular mapping of neuronal architecture using STORM microscopy and new fluorescent probes for SMLM imaging

“…MemBright has been widely adopted by the extracellular vesicles community 51 to track extracellular vesicles both in vitro or in vivo 61 – 81 in hippocampal 63 or cortical neurons, 79 zebrafish, 62 , 67 , 72 breast cancer cells or tumours, 66 , 71 , 80 myotubes, 82 and red blood cells 74 , 76 …”

The Discovery of Extracellular Vesicles and Their Emergence as a Next-Generation Therapy

“…Third, EVs have a remarkable capacity to transverse biological barriers, such as blood-brain barriers or endothelial barriers. 146–148 Although this feature holds significant therapeutic implications, how EVs accomplish this feat is still being elucidated, and whether this is true in higher primates is being debated and in humans, unknown. Proposed mechanisms include transcytosis (internalized by endothelial cells and subsequently released across the barrier) and EV-mediated inflammation that disrupts tight junctions between endothelial cells and compromises barrier permeability.…”