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oai:recercat.cat:2445/2124482025-12-05T09:21:24Zcom_2072_1057col_2072_478799col_2072_478916col_2072_478917

Endothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammation Esteve Codina, Anna Arribas, Víctor Onetti, Yara Ramiro Pareta, Marina Villacampa, Pilar Beck, Heike Alberola, Mariona Merkel, Angelika Sperandio, Markus Martínez Estrada, Ofelia María Schmid, Bettina Montañez, Eloi Endoteli Angiogènesi Animals Proteïnes Endothelium Neovascularization Animals Proteins TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA-binding protein that regulates gene expression, and its malfunction in neurons has been causally associated with multiple neurodegenerative disorders. Although progress has been made in understanding the functions of TDP-43 in neurons, little is known about its roles in endothelial cells (ECs), angiogenesis, and vascular function. Using inducible EC-specific TDP-43-KO mice, we showed that TDP-43 is required for sprouting angiogenesis, vascular barrier integrity, and blood vessel stability. Postnatal EC-specific deletion of TDP-43 led to retinal hypovascularization due to defects in vessel sprouting associated with reduced EC proliferation and migration. In mature blood vessels, loss of TDP-43 disrupted the blood-brain barrier and triggered vascular degeneration. These vascular defects were associated with an inflammatory response in the CNS with activation of microglia and astrocytes. Mechanistically, deletion of TDP-43 disrupted the fibronectin matrix around sprouting vessels and reduced β-catenin signaling in ECs. Together, our results indicate that TDP-43 is essential for the formation of a stable and mature vasculature. 2024-06-04T18:07:25Z 2024-06-04T18:07:25Z 2024-02-01 2024-06-04T18:07:30Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion 2379-3708 https://hdl.handle.net/2445/212448 746290 38300714 eng Reproducció del document publicat a: https://doi.org/10.1172/jci.insight.177819 JCI Insight, 2024, vol. 9, num.5 https://doi.org/10.1172/jci.insight.177819 (c) American Society for Clinical Investigation, 2024 info:eu-repo/semantics/openAccess 19 p. application/pdf American Society for Clinical Investigation Articles publicats en revistes (Ciències Fisiològiques)