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

Savage, Aaron M.; Kurusamy, Sathishkumar; Chen, Yan; Jiang, Zhen; Chhabria, Karishma; MacDonald, Ryan B.; Kim, Hyejeong R.; Wilson, Heather L.; van Eeden, Fredericus J. M.; Chico, Timothy J. A.; Armesilla, Angel L.; Wilkinson, Robert N.

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

• Journal Article Type: Article
• Acceptance Date: Jan 21, 2019
• Online Publication Date: Feb 13, 2019
• Publication Date: Feb 13, 2019
• Deposit Date: Nov 12, 2019
• Publicly Available Date: Nov 12, 2019
• Journal: Nature Communications
• Electronic ISSN: 2041-1723
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 10
• Article Number: 732
• DOI: https://doi.org/10.1038/s41467-019-08590-7
• Public URL: https://nottingham-repository.worktribe.com/output/3230503
• Publisher URL: https://www.nature.com/articles/s41467-019-08590-7
• Additional Information: Received: 15 August 2017; Accepted: 21 January 2019; First Online: 13 February 2019; : The authors declare no competing interests.