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Endothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammation
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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.
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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. Endothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammation. _JCI Insight_. 2024. Vol. 9, núm. 5. [consulta: 24 de gener de 2026]. ISSN: 2379-3708. [Disponible a: https://hdl.handle.net/2445/212448]