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

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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Item Type:	Article
Authors/Creators:	Savage, A.M. Kurusamy, S. Chen, Y. Jiang, Z. Chhabria, K. MacDonald, R.B. Kim, H.R. Wilson, H.L. van Eeden, F.J.M. Armesilla, A.L. Chico, T.J.A. Wilkinson, R.N. https://orcid.org/0000-0003-2706-316X
Copyright, Publisher and Additional Information:	© 2019 The Authors. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Published: 13 February 2019 Published (online): 13 February 2019 Accepted: 21 January 2019
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Infection and Immunity (Sheffield)
Funding Information:	Funder Grant number ROYAL SOCIETY RG120564 BRITISH HEART FOUNDATION IG/15/1/31328 DIABETES UK 17/0005678 BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL (BBSRC) BB/R015457/1
Depositing User:	Symplectic Sheffield
Date Deposited:	14 Feb 2019 16:42
Last Modified:	15 Feb 2019 04:50
Published Version:	https://doi.org/10.1038/s41467-019-08590-7
Status:	Published
Publisher:	Nature Research
Refereed:	Yes
Identification Number:	10.1038/s41467-019-08590-7
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:142525

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

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