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

Arribas, Víctor; Onetti, Yara; Ramiro Pareta, Marina; Villacampa, Pilar; Beck, Heike; Alberola i Pla, Mariona; Esteve-Codina, Anna; Merkel, Angelika; Sperandio, Markus; Martínez Estrada, Ofelia M.; Schmid, Bettina; Montanez, Eloi

doi:http://dx.doi.org/10.1172/jci.insight.177819

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

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Arribas V, Onetti Y, Ramiro-Pareta M, Villacampa P, Beck H, Alberola M, et al. Endothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammation. JCI Insight. 2024 Feb 1;9(5):e177819. DOI: 10.1172/jci.insight.177819

Abstract

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.