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

Aaron M. Savage, Sathishkumar Kurusamy, Yan Chen, Zhen Jiang, Karishma Chhabria, Ryan B. MacDonald, Hyejeong R. Kim, Heather L. Wilson, Fredericus J. M. Eeden, Angel L. Armesilla, Timothy J. A. Chico and Robert N. Wilkinson ()
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Aaron M. Savage: Medical School, University of Sheffield
Sathishkumar Kurusamy: University of Wolverhampton
Yan Chen: Medical School, University of Sheffield
Zhen Jiang: Medical School, University of Sheffield
Karishma Chhabria: Medical School, University of Sheffield
Ryan B. MacDonald: Medical School, University of Sheffield
Hyejeong R. Kim: University of Sheffield
Heather L. Wilson: Medical School, University of Sheffield
Fredericus J. M. Eeden: University of Sheffield
Angel L. Armesilla: University of Wolverhampton
Timothy J. A. Chico: Medical School, University of Sheffield
Robert N. Wilkinson: Medical School, University of Sheffield

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08590-7

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