Endothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammation

• Published in: JCI insight 2024-02, Vol.9 (5)
• Main Authors: Arribas, Víctor, Onetti, Yara, Ramiro-Pareta, Marina, Villacampa, Pilar, Beck, Heike, Alberola, Mariona, Esteve-Codina, Anna, Merkel, Angelika, Sperandio, Markus, Martínez-Estrada, Ofelia M, Schmid, Bettina, Montanez, Eloi
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Endothelial Cells - metabolism; Mice; Neovascularization, Physiologic - genetics; Neuroinflammatory Diseases
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.177819

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.