CMTM4 regulates angiogenesis by promoting cell surface recycling of VE-cadherin to endothelial adherens junctions View Full Text


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Article Info

DATE

2018-08-10

AUTHORS

Ihsan Chrifi, Laura Louzao-Martinez, Maarten M. Brandt, Christian G. M. van Dijk, Petra E. Bürgisser, Changbin Zhu, Johan M. Kros, Marianne C. Verhaar, Dirk J. Duncker, Caroline Cheng

ABSTRACT

Vascular endothelial (VE) cadherin is a key component of endothelial adherens junctions (AJs) and plays an important role in maintaining vascular integrity. Endocytosis of VE-cadherin regulates junctional strength and a decrease of surface VE-cadherin reduces vascular stability. However, disruption of AJs is also a requirement for vascular sprouting. Identifying novel regulators of endothelial endocytosis could enhance our understanding of angiogenesis. Here, we evaluated the angiogenic potential of (CKLF-like MARVEL transmembrane domain 4) CMTM4 and assessed in which molecular pathway CMTM4 is involved during angiogenesis. Using a 3D vascular assay composed of GFP-labeled HUVECs and dsRED-labeled pericytes, we demonstrated in vitro that siRNA-mediated CMTM4 silencing impairs vascular sprouting. In vivo, CMTM4 silencing by morpholino injection in zebrafish larvae inhibits intersomitic vessel growth. Intracellular staining revealed that CMTM4 colocalizes with Rab4+ and Rab7+ vesicles, both markers of the endocytic trafficking pathway. CMTM4 colocalizes with both membrane-bound and internalized VE-cadherin. Adenovirus-mediated CMTM4 overexpression enhances the endothelial endocytic pathway, in particular the rapid recycling pathway, shown by an increase in early endosomal antigen-1 positive (EEA1+), Rab4+, Rab11+ , and Rab7+ vesicles. CMTM4 overexpression enhances membrane-bound VE-cadherin internalization, whereas CMTM4 knockdown decreases internalization of VE-cadherin. CMTM4 overexpression promotes endothelial barrier function, shown by an increase in recovery of transendothelial electrical resistance (TEER) after thrombin stimulation. We have identified in this study a novel regulatory function for CMTM4 in angiogenesis. CMTM4 plays an important role in the turnover of membrane-bound VE-cadherin at AJs, mediating endothelial barrier function and controlling vascular sprouting. More... »

PAGES

75-93

References to SciGraph publications

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  • 2003-06. Angiogenesis in health and disease in NATURE MEDICINE
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  • 2010-02-02. Adherens junctions connect stress fibres between adjacent endothelial cells in BMC BIOLOGY
  • 2010-03-04. Identification and characterization of CMTM4, a novel gene with inhibitory effects on HeLa cell growth through Inducing G2/M phase accumulation in MOLECULES AND CELLS
  • 2014-11-12. CMTM5 is reduced in prostate cancer and inhibits cancer cell growth in vitro and in vivo in CLINICAL AND TRANSLATIONAL ONCOLOGY
  • 2009-07-15. Rab GTPases as coordinators of vesicle traffic in NATURE REVIEWS MOLECULAR CELL BIOLOGY
  • 2006-10-22. VEGF controls endothelial-cell permeability by promoting the β-arrestin-dependent endocytosis of VE-cadherin in NATURE CELL BIOLOGY
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  • 2015-10-16. CMTM4 is frequently downregulated and functions as a tumour suppressor in clear cell renal cell carcinoma in JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
  • 2017-12-20. Polarized actin and VE-cadherin dynamics regulate junctional remodelling and cell migration during sprouting angiogenesis in NATURE COMMUNICATIONS
  • 2000-10. Effective targeted gene ‘knockdown’ in zebrafish in NATURE GENETICS
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1007/s10456-018-9638-1

    DOI

    http://dx.doi.org/10.1007/s10456-018-9638-1

    DIMENSIONS

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30097810


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    28 schema:description Vascular endothelial (VE) cadherin is a key component of endothelial adherens junctions (AJs) and plays an important role in maintaining vascular integrity. Endocytosis of VE-cadherin regulates junctional strength and a decrease of surface VE-cadherin reduces vascular stability. However, disruption of AJs is also a requirement for vascular sprouting. Identifying novel regulators of endothelial endocytosis could enhance our understanding of angiogenesis. Here, we evaluated the angiogenic potential of (CKLF-like MARVEL transmembrane domain 4) CMTM4 and assessed in which molecular pathway CMTM4 is involved during angiogenesis. Using a 3D vascular assay composed of GFP-labeled HUVECs and dsRED-labeled pericytes, we demonstrated in vitro that siRNA-mediated CMTM4 silencing impairs vascular sprouting. In vivo, CMTM4 silencing by morpholino injection in zebrafish larvae inhibits intersomitic vessel growth. Intracellular staining revealed that CMTM4 colocalizes with Rab4<sup>+</sup> and Rab7<sup>+</sup> vesicles, both markers of the endocytic trafficking pathway. CMTM4 colocalizes with both membrane-bound and internalized VE-cadherin. Adenovirus-mediated CMTM4 overexpression enhances the endothelial endocytic pathway, in particular the rapid recycling pathway, shown by an increase in early endosomal antigen-1 positive (EEA1<sup>+</sup>), Rab4<sup>+</sup>, Rab11<sup>+</sup> , and Rab7<sup>+</sup> vesicles. CMTM4 overexpression enhances membrane-bound VE-cadherin internalization, whereas CMTM4 knockdown decreases internalization of VE-cadherin. CMTM4 overexpression promotes endothelial barrier function, shown by an increase in recovery of transendothelial electrical resistance (TEER) after thrombin stimulation. We have identified in this study a novel regulatory function for CMTM4 in angiogenesis. CMTM4 plays an important role in the turnover of membrane-bound VE-cadherin at AJs, mediating endothelial barrier function and controlling vascular sprouting.
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