The blood-brain barrier (BBB), formed primarily by specialized brain endothelial cells (BEC), is essential nutrient transport, signal transduction, immune cell migration, and pathogen restriction. Although these functions are influenced by the identity and abundance of cell-membrane proteins, the role of protein endocytic turnover rate (ETOR, the dynamics of protein internalization, recycling, and degradation) governing BBB physiology remains poorly understood. Using in vitro proteomics, we analyzed ETOR across approximately 1,000 proteins in rat endothelial cells under healthy and pathological conditions to investigate BBB specialization and dysfunction. We found that BEC display a distinct ETOR profile that differentiates them from ripheral endothelial cells beyond membrane protein composition. Inflammatory conditions shifted the BEC ETOR profile towards a peripheral phenotype. Moreover, inflammation-induced abundance changes highlighted immune-response proteins, whereas ETOR alterations identified proteins associated with vascular remodeling. These findings establish ETOR as a dynamic regulator of BBB specialization and inflammatory dysfunction.
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Tomas-Sitjes, Alba, Arauz-Garofalo, Gianluca, Gay, Marina, Jario, Sonia, Vilaseca, Marta, Schastlivaia, Valentina, Kessen, Maaike, Manicardi, Nicola, Battaglia, Giuseppe, Gonzalez-Carter, Daniel, (2026). Endocytic turnover of endothelial cell-membrane proteins as a driver of rat blood-brain barrier specialization and dysfunction iScience 29, 116231 