2. Academic Validation
  3. tmem33 is essential for VEGF-mediated endothelial calcium oscillations and angiogenesis

tmem33 is essential for VEGF-mediated endothelial calcium oscillations and angiogenesis

  • Nat Commun. 2019 Feb 13;10(1):732. doi: 10.1038/s41467-019-08590-7.
Aaron M Savage 1 2,  Sathishkumar Kurusamy 3,  Yan Chen 1 2,  Zhen Jiang 1 2,  Karishma Chhabria 1 2,  Ryan B MacDonald 1 2,  Hyejeong R Kim 2 4,  Heather L Wilson 1 2,  Fredericus J M van Eeden 2 4 5,  Angel L Armesilla 3,  Timothy J A Chico 1 2,  Robert N Wilkinson 6 7 8
Affiliations

Affiliations

  • 1 Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UK.
  • 2 The Bateson Centre, University of Sheffield, Sheffield, UK.
  • 3 Cardiovascular Molecular Pharmacology Laboratory, Faculty of Science and Engineering, Research Institute in Healthcare Science, School of Pharmacy, University of Wolverhampton, Wolverhampton, UK.
  • 4 Department of Biomedical Science, University of Sheffield, Sheffield, UK.
  • 5 Sheffield CRISPRi Facility, Sheffield, UK.
  • 6 Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UK. Robert.wilkinson@sheffield.ac.uk.
  • 7 The Bateson Centre, University of Sheffield, Sheffield, UK. Robert.wilkinson@sheffield.ac.uk.
  • 8 Sheffield CRISPRi Facility, Sheffield, UK. Robert.wilkinson@sheffield.ac.uk.
PMID: 30760708 DOI: 10.1038/s41467-019-08590-7
Abstract

Angiogenesis requires co-ordination of multiple signalling inputs to regulate the behaviour of endothelial cells (ECs) as they form vascular networks. Vascular endothelial growth factor (VEGF) is essential for angiogenesis and induces downstream signalling pathways including increased cytosolic calcium levels. Here we show that transmembrane protein 33 (tmem33), which has no known function in multicellular organisms, is essential to mediate effects of VEGF in both zebrafish and human ECs. We find that tmem33 localises to the endoplasmic reticulum in zebrafish ECs and is required for cytosolic calcium oscillations in response to Vegfa. tmem33-mediated endothelial calcium oscillations are critical for formation of endothelial tip cell filopodia and EC migration. Global or endothelial-cell-specific knockdown of tmem33 impairs multiple downstream effects of VEGF including ERK phosphorylation, Notch signalling and embryonic vascular development. These studies reveal a hitherto unsuspected role for tmem33 and calcium oscillations in the regulation of vascular development.

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