TY  - JOUR
AU  - Arribas, Víctor
AU  - Onetti, Yara
AU  - Ramiro-Pareta, Marina
AU  - Villacampa, Pilar
AU  - Beck, Heike
AU  - Alberola, Mariona
AU  - Esteve-Codina, Anna
AU  - Merkel, Angelika
AU  - Sperandio, Markus
AU  - Martínez-Estrada, Ofelia M
AU  - Schmid, Bettina
AU  - Montanez, Eloi
TI  - Endothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammation.
JO  - JCI insight
VL  - 9
IS  - 5
SN  - 2379-3708
CY  - Ann Arbor, Michigan
PB  - JCI Insight
M1  - DZNE-2024-00271
SP  - e177819
PY  - 2024
AB  - 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.
KW  - Mice
KW  - Animals
KW  - Endothelial Cells: metabolism
KW  - Neuroinflammatory Diseases
KW  - Angiogenesis
KW  - Neovascularization, Physiologic: genetics
KW  - DNA-Binding Proteins: genetics
KW  - DNA-Binding Proteins: metabolism
KW  - Angiogenesis (Other)
KW  - Endothelial cells (Other)
KW  - Vascular biology (Other)
KW  - DNA-Binding Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC11143933
C6  - pmid:38300714
DO  - DOI:10.1172/jci.insight.177819
UR  - https://pub.dzne.de/record/268530
ER  -