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TGF-? signaling in endothelial cells, but not neuroepithelial cells, is essential for cerebral vascular development.

ABSTRACT: The various organs of the body harbor blood vessel networks that display unique structural and functional features; however, the mechanisms that control organ-specific vascular development and physiology remain mostly unknown. In the developing mouse brain, ?v?8 integrin-mediated TGF-? activation and signaling is essential for normal blood vessel growth and sprouting. Whether integrins activate TGF-? signaling pathways in vascular endothelial cells (ECs), neural cells, or both, has yet to be determined. Here, we have generated and characterized mice in which TGF-? receptors are specifically deleted in neuroepithelial cells via Nestin-Cre, or in ECs via a novel Cre transgenic strain (Alk1(GFPCre)) in which Cre is expressed under control of the endogenous activin receptor-like kinase 1 (Alk1) promoter. We report that deletion of Tgfbr2 in the neuroepithelium does not impact brain vascular development. In contrast, selective deletion of the Tgfbr2 or Alk5 genes in ECs result in embryonic lethality because of brain-specific vascular pathologies, including blood vessel morphogenesis and intracerebral hemorrhage. These data reveal for the first time that ?v?8 integrin-activated TGF-?s regulate angiogenesis in the developing brain via paracrine signaling to ECs.

SUBMITTER: Nguyen HL

PROVIDER: S-EPMC3802535 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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TGF-β signaling in endothelial cells, but not neuroepithelial cells, is essential for cerebral vascular development.

Nguyen Ha-Long HL Lee Young Jae YJ Shin Jaekyung J Lee Eunji E Park Sung Ok SO McCarty Joseph H JH Oh S Paul SP

Laboratory investigation; a journal of technical methods and pathology 20110829 11

The various organs of the body harbor blood vessel networks that display unique structural and functional features; however, the mechanisms that control organ-specific vascular development and physiology remain mostly unknown. In the developing mouse brain, αvβ8 integrin-mediated TGF-β activation and signaling is essential for normal blood vessel growth and sprouting. Whether integrins activate TGF-β signaling pathways in vascular endothelial cells (ECs), neural cells, or both, has yet to be det ...[more]

PMID: 21876535

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Project description:BackgroundNDRG-1 (N-myc downstream-regulated gene 1) is a member of NDRG family that plays essential roles in cell differentiation, proliferation, and stress responses. Although the expression of NDRG1 is regulated by fluid shear stress, its roles in vascular biology remain poorly understood. The purpose of the study is to determine the functional significance of NDRG1 in vascular inflammation and remodeling.Methods and resultsBy using quantitative polymerase chain reaction, western blot, and immunohistochemistry, we demonstrate that the expression of NDRG1 is markedly increased in cytokine-stimulated endothelial cells and in human and mouse atherosclerotic lesions. To determine the role of NDRG1 in endothelial activation, we performed loss-of-function studies using NDRG1 short hairpin RNA. Our results demonstrate that NDRG1 knockdown by lentivirus bearing NDRG1 short hairpin RNA substantially attenuates both IL-1β (interleukin-1β) and TNF-α (tumor necrosis factor-α)-induced expression of cytokines/chemokines and adhesion molecules. Intriguingly, inhibition of NDRG1 also significantly attenuates the expression of procoagulant molecules, such as PAI-1 (plasminogen activator inhibitor type 1) and TF (tissue factor), and increases the expression of TM (thrombomodulin) and t-PA (tissue-type plasminogen activator), thus exerting potent antithrombotic effects in endothelial cells. Mechanistically, we showed that NDRG1 interacts with orphan Nur77 (nuclear receptor) and functionally inhibits the transcriptional activity of Nur77 and NF-κB (nuclear factor Kappa B) in endothelial cells. Moreover, in NDRG1 knockdown cells, both cytokine-induced mitogen-activated protein kinase activation, c-Jun phosphorylation, and AP-1 (activator protein 1) transcriptional activity are substantially inhibited. Neointima and atherosclerosis formation induced by carotid artery ligation and arterial thrombosis were markedly attenuated in endothelial cell-specific NDRG1 knockout mice compared with their wild-type littermates.ConclusionsOur results for the first time identify NDRG1 as a critical mediator implicated in regulating endothelial inflammation, thrombotic responses, and vascular remodeling, and suggest that inhibition of NDRG1 may represent a novel therapeutic strategy for inflammatory vascular diseases, such as atherothrombosis and restenosis.

Dataset Information

TGF-? signaling in endothelial cells, but not neuroepithelial cells, is essential for cerebral vascular development.

Publications

TGF-β signaling in endothelial cells, but not neuroepithelial cells, is essential for cerebral vascular development.

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