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

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

PROVIDER: PRJNA1067587 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27681700_1.fastq.gz	Fastqsanger.gz
	SRR27681700_2.fastq.gz	Fastqsanger.gz
	SRR27681701_1.fastq.gz	Fastqsanger.gz
	SRR27681701_2.fastq.gz	Fastqsanger.gz
	SRR27681702_1.fastq.gz	Fastqsanger.gz

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

Project description: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 role in endothelial cells (ECs), angiogenesis and vascular function. Using inducible EC-specific TDP-43 knockout mice, we show that TDP-43 is required for sprouting angiogenesis, vascular barrier integrity and blood vessel stability. Postnatal EC-specific deletion of TDP-43 leads to retinal hypovascularization due to defects in vessel sprouting associated with reduced EC proliferation and migration. In mature blood vessels, loss of TDP-43 disrupts the blood-brain barrier and triggers vascular degeneration. These vascular defects are associated with an inflammatory response in the central-nervous system with activation of microglia and astrocytes. Mechanistically, deletion of TDP-43 disrupts fibronectin matrix around sprouting vessels and reduces -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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Cx40 Suppresses Sprouting Angiogenesis In Vitro

Project description:Blood vessels are highly organized and form during development through a series of complex processes that include vasculogenesis, sprouting angiogenesis, and vessel remodeling. Several gap junction proteins (termed connexins, Cx) – including Cx40 (GJA5) – are expressed in vascular endothelium early during vessel development and are critical for establishment of a healthy vasculature. However, Cx40’s specific role in regulating vessel growth remains uncertain: while previous studies have shown that developmental and cancer-associated neovascularization is reduced in Cx40-knockout mice, Cx40 knockout in zebrafish embryos enhances intersegmental vessel growth. Thus, in the current study, our aim was to identify Cx40’s specific role in sprouting angiogenesis. First, we used a vessel-on-a-chip microphysiological model to confirm Cx40’s overall necessity for microvessel network development. Next, we used the fibrin gel bead assay – a three-dimensional in vitro model of sprouting angiogenesis – to assess Cx40’s necessity for this process. We found that Cx40 knockdown in endothelial cells drives more aggressive sprouting angiogenesis in association with increased endothelial cell proliferation. By contrast, using Electrical Cell-substrate Impedance Sensing (ECIS) we observed no effect of Cx40 knockdown on endothelial cell migration. Lastly, we found that Cx37 (GJA4) is reduced in Cx40- deficient endothelial cells, and that targeted silencing of Cx37 alone produces a more aggressive, hyper-sprouting phenotype compared to control or Cx40 knockdown endothelial cells. Taken together, our data argue that Cx40 plays multiple roles during vessel growth, including to specifically limit sprouting angiogenesis, and that this may occur (at least in part) through regulation of endothelial Cx37 levels.

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Loss of TDP-43 causes ectopic endothelial sprouting and migration defects through increased fibronectin, vcam 1 and integrin α4/β1

Project description:Aggregation of the Tar DNA-binding protein of 43 kDa (TDP-43) is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and likely contributes to disease by loss of nuclear function. Analysis of TDP-43 function in knockout zebrafish identified an endothelial directional migration and hypersprouting phenotype during development prior lethality. In human umbilical vein cells (HUVEC) the loss of TDP-43 leads to hyperbranching. We identified elevated expression of FIBRONECTIN 1 (FN1), the VASCULAR CELL ADHESION MOLECULE 1 (VCAM1), as well as their receptor INTEGRIN α4β1 (ITGA4B1) in HUVEC cells. Importantly, reducing the levels of ITGA4, FN1, and VCAM1 homologues in the TDP-43 loss-of-function zebrafish rescues the angiogenic defects indicating the conservation of human and zebrafish TDP-43 function during angiogenesis. Our study identifies a novel pathway regulated by TDP-43 important for angiogenesis during development.

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Cx40 Suppresses Sprouting Angiogenesis In Vitro

Project description:Cx40 Suppresses Sprouting Angiogenesis In Vitro

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