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000268530 1001_ $$aArribas, Víctor$$b0
000268530 245__ $$aEndothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammation.
000268530 260__ $$aAnn Arbor, Michigan$$bJCI Insight$$c2024
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000268530 520__ $$aTAR DNA-binding protein 43 (TDP-43) is a DNA/RNA-binding protein that regulates gene expression, and its malfunction in neurons has been causally associated with multiple neurodegenerative disorders. Although progress has been made in understanding the functions of TDP-43 in neurons, little is known about its roles in endothelial cells (ECs), angiogenesis, and vascular function. Using inducible EC-specific TDP-43-KO mice, we showed that TDP-43 is required for sprouting angiogenesis, vascular barrier integrity, and blood vessel stability. Postnatal EC-specific deletion of TDP-43 led to retinal hypovascularization due to defects in vessel sprouting associated with reduced EC proliferation and migration. In mature blood vessels, loss of TDP-43 disrupted the blood-brain barrier and triggered vascular degeneration. These vascular defects were associated with an inflammatory response in the CNS with activation of microglia and astrocytes. Mechanistically, deletion of TDP-43 disrupted the fibronectin matrix around sprouting vessels and reduced β-catenin signaling in ECs. Together, our results indicate that TDP-43 is essential for the formation of a stable and mature vasculature.
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000268530 650_7 $$2Other$$aAngiogenesis
000268530 650_7 $$2Other$$aEndothelial cells
000268530 650_7 $$2Other$$aVascular biology
000268530 650_7 $$2NLM Chemicals$$aDNA-Binding Proteins
000268530 650_2 $$2MeSH$$aMice
000268530 650_2 $$2MeSH$$aAnimals
000268530 650_2 $$2MeSH$$aEndothelial Cells: metabolism
000268530 650_2 $$2MeSH$$aNeuroinflammatory Diseases
000268530 650_2 $$2MeSH$$aAngiogenesis
000268530 650_2 $$2MeSH$$aNeovascularization, Physiologic: genetics
000268530 650_2 $$2MeSH$$aDNA-Binding Proteins: genetics
000268530 650_2 $$2MeSH$$aDNA-Binding Proteins: metabolism
000268530 7001_ $$aOnetti, Yara$$b1
000268530 7001_ $$aRamiro-Pareta, Marina$$b2
000268530 7001_ $$aVillacampa, Pilar$$b3
000268530 7001_ $$aBeck, Heike$$b4
000268530 7001_ $$aAlberola, Mariona$$b5
000268530 7001_ $$aEsteve-Codina, Anna$$b6
000268530 7001_ $$aMerkel, Angelika$$b7
000268530 7001_ $$aSperandio, Markus$$b8
000268530 7001_ $$aMartínez-Estrada, Ofelia M$$b9
000268530 7001_ $$0P:(DE-2719)2241638$$aSchmid, Bettina$$b10$$udzne
000268530 7001_ $$aMontanez, Eloi$$b11
000268530 773__ $$0PERI:(DE-600)2874757-4$$a10.1172/jci.insight.177819$$gVol. 9, no. 5$$n5$$pe177819$$tJCI insight$$v9$$x2379-3708$$y2024
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