Journal Article

DZNE-2024-00271

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Endothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammation.

Arribas, V. ; Onetti, Y. ; Ramiro-Pareta, M. ; Villacampa, P. ; Beck, H. ; Alberola, M. ; Esteve-Codina, A. ; Merkel, A. ; Sperandio, M. ; Martínez-Estrada, O. M. ; Schmid, B.DZNE* ; Montanez, E.

2024
JCI Insight Ann Arbor, Michigan

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Please use a persistent id in citations: 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.

Keyword(s): Mice (MeSH) ; Animals (MeSH) ; Endothelial Cells: metabolism (MeSH) ; Neuroinflammatory Diseases (MeSH) ; Angiogenesis (MeSH) ; Neovascularization, Physiologic: genetics (MeSH) ; DNA-Binding Proteins: genetics (MeSH) ; DNA-Binding Proteins: metabolism (MeSH) ; Angiogenesis ; Endothelial cells ; Vascular biology ; DNA-Binding Proteins

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Contributing Institute(s):

1. Fish Core Unit (AG Schmid)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2024

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Database coverage:
; ; ; ; Article Processing Charges ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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