ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Embryonic Development
Disruption of Swell1/VRAC Function Impairs Initial Hemodynamics and Activates Compensatory Leukotriene Signaling in Zebrafish Circulation Development
Provisionally accepted
- 1National Taiwan University, Taipei, Taiwan
- 2Taipei Medical University, Taipei City, Taiwan
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Volume-regulated anion channels (VRACs) maintain cell-volume homeostasis, and SWELL1 is their essential subunit. Here, we show that VRAC/Swell1 also regulates initial hemodynamics and vascular development in zebrafish. Stable swell1a and swell1b mutant zebrafish lines were established. In SWELL1-KO HAP1 cells, VRAC currents were rescued by wild-type, but not mutant, zebrafish swell1a or swell1b cDNA, confirming the alleles' loss-of-function nature. Microangiography and Tg(fli1a:eGFP) imaging revealed hypovolemia, reduced flow, and delayed vessel sprouting by 30 hpf, with severity proportional to allele dosage and partial recovery by 72 hpf. Whole-embryo transcriptomics highlighted up-regulation of arachidonic-acid metabolism, especially the 5-lipoxygenase (5LO) axis. Pharmacological 5LO inhibition or the receptor cyslt1r knockdown aggravated circulatory defects, whereas leukotriene C4 treatment improved hemodynamics, indicating compensatory 5LO signalling. Thus, Swell1-dependent VRAC activity underpins embryonic hemodynamic stability, and 5LO-derived mediators partially buffer its loss. These findings link ion-channel function to lipid signalling in vascular development and suggest VRAC/Swell1-5LO cross-talk as a therapeutic target for blood-flow disorders.
Keywords: 5-lipoxygenase, arachidonic acid metabolism, circulatory system development, LRRC8A, swel1, VRAC, Zebrafish
Received: 06 Oct 2025; Accepted: 28 Nov 2025.
Copyright: © 2025 Tseng, Chang, Huang-Fu and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Wei-Chun Huang-Fu
I-Hsuan Liu
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.