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  • 1
    Online Resource
    Online Resource
    Caveolae-mediated Tie2 signaling contributes to CCM pathogenesis in a brain endothelial cell-specific Pdcd10-deficient mouse model
    Springer Science and Business Media LLC ; 2021
    In:  Nature Communications Vol. 12, No. 1 ( 2021-01-25)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2021-01-25)
    Abstract: Cerebral cavernous malformations (CCMs) are vascular abnormalities that primarily occur in adulthood and cause cerebral hemorrhage, stroke, and seizures. CCMs are thought to be initiated by endothelial cell (EC) loss of any one of the three Ccm genes: CCM1 (KRIT1), CCM2 (OSM), or CCM3 (PDCD10) . Here we report that mice with a brain EC-specific deletion of Pdcd10 ( Pdcd10 BECKO ) survive up to 6-12 months and develop bona fide CCM lesions in all regions of brain, allowing us to visualize the vascular dynamics of CCM lesions using transcranial two-photon microscopy. This approach reveals that CCMs initiate from protrusion at the level of capillary and post-capillary venules with gradual dissociation of pericytes. Microvascular beds in lesions are hyper-permeable, and these disorganized structures present endomucin-positive ECs and α-smooth muscle actin-positive pericytes. Caveolae in the endothelium of Pdcd10 BECKO lesions are drastically increased, enhancing Tie2 signaling in Ccm3-deficient ECs. Moreover, genetic deletion of caveolin-1 or pharmacological blockade of Tie2 signaling effectively normalizes microvascular structure and barrier function with attenuated EC-pericyte disassociation and CCM lesion formation in Pdcd10 BECKO mice. Our study establishes a chronic CCM model and uncovers a mechanism by which CCM3 mutation-induced caveolae-Tie2 signaling contributes to CCM pathogenesis.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-020-20774-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2553671-0
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  • 2
    Online Resource
    Online Resource
    Mitochondrial dysfunction induces ALK5-SMAD2-mediated hypovascularization and arteriovenous malformations in mouse retinas
    Springer Science and Business Media LLC ; 2022
    In:  Nature Communications Vol. 13, No. 1 ( 2022-12-10)
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    In: Nature Communications, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2022-12-10)
    Abstract: Although mitochondrial activity is critical for angiogenesis, its mechanism is not entirely clear. Here we show that mice with endothelial deficiency of any one of the three nuclear genes encoding for mitochondrial proteins, transcriptional factor (TFAM), respiratory complex IV component (COX10), or redox protein thioredoxin 2 (TRX2), exhibit retarded retinal vessel growth and arteriovenous malformations (AVM). Single-cell RNA-seq analyses indicate that retinal ECs from the three mutant mice have increased TGFβ signaling and altered gene expressions associated with vascular maturation and extracellular matrix, correlating with vascular malformation and increased basement membrane thickening in microvesels of mutant retinas. Mechanistic studies suggest that mitochondrial dysfunction from Tfam , Cox10 , or Trx2 depletion induces a mitochondrial localization and MAPKs-mediated phosphorylation of SMAD2, leading to enhanced ALK5-SMAD2 signaling. Importantly, pharmacological blockade of ALK5 signaling or genetic deficiency of SMAD2 prevented retinal vessel growth retardation and AVM in all three mutant mice. Our studies uncover a novel mechanism whereby mitochondrial dysfunction via the ALK5-SMAD2 signaling induces retinal vascular malformations, and have therapeutic values for the alleviation of angiogenesis-associated human retinal diseases.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-022-35262-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2553671-0
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  • 3
    Online Resource
    Online Resource
    CCM3 Loss-Induced Lymphatic Defect Is Mediated by the Augmented VEGFR3-ERK1/2 Signaling
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 41, No. 12 ( 2021-12), p. 2943-2960
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 41, No. 12 ( 2021-12), p. 2943-2960
    Abstract: Cerebral cavernous malformations (CCMs) can happen anywhere in the body, although they most commonly produce symptoms in the brain. The role of CCM genes in other vascular beds outside the brain and retina is not well-examined, although the 3 CCM-associated genes ( CCM1 , CCM2 , and CCM3 ) are ubiquitously expressed in all tissues. We aimed to determine the role of CCM gene in lymphatics. Approach and Results: Mice with an inducible pan–endothelial cell (EC) or lymphatic EC deletion of Ccm3 ( Pdcd10 ECKO or Pdcd10 LECKO ) exhibit dilated lymphatic capillaries and collecting vessels with abnormal valve structure. Morphological alterations were correlated with lymphatic dysfunction in Pdcd10 LECKO mice as determined by Evans blue dye and fluorescein isothiocyanate(FITC)-dextran transport assays. Pdcd10 LECKO lymphatics had increased VEGFR3 (vascular endothelial growth factor receptor-3)-ERK1/2 (extracellular signal-regulated kinase 1/2) signaling with lymphatic hyperplasia. Mechanistic studies suggested that VEGFR3 is primarily regulated at a transcriptional level in Ccm3-deficient lymphatic ECs, in an NF-κB (nuclear factor κB)–dependent manner. CCM3 binds to importin alpha 2/KPNA2 (karyopherin subunit alpha 2), and a CCM3 deletion releases KPNA2 to activate NF-κB P65 by facilitating its nuclear translocation and P65-dependent VEGFR3 transcription. Moreover, increased VEGFR3 in lymphatic EC preferentially activates ERK1/2 signaling, which is critical for lymphatic EC proliferation. Importantly, inhibition of VEGFR3 or ERK1/2 rescued the lymphatic defects in structure and function. Conclusions: Our data demonstrate that CCM3 deletion augments the VEGFR3-ERK1/2 signaling in lymphatic EC that drives lymphatic hyperplasia and malformation and warrant further investigation on the potential clinical relevance of lymphatic dysfunction in patients with CCM.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.121.316707
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 1494427-3
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