# Disruption of Swell1/VRAC function impairs initial hemodynamics and activates compensatory leukotriene signaling in zebrafish circulation development

## TL;DR

This study shows that a specific ion channel, VRAC/Swell1, is important for early blood flow and vessel development in zebrafish, and its loss activates a compensatory signaling pathway.

## Contribution

The study reveals a novel role for VRAC/Swell1 in embryonic hemodynamics and identifies a compensatory leukotriene signaling pathway in vascular development.

## Key findings

- Disruption of Swell1/VRAC function leads to hypovolemia, reduced blood flow, and delayed vessel sprouting in zebrafish embryos.
- Loss of Swell1 activates compensatory leukotriene signaling via the 5LO axis to partially buffer circulatory defects.
- Leukotriene C4 treatment improves hemodynamics in Swell1-deficient zebrafish, suggesting a potential therapeutic strategy.

## Abstract

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 upregulation 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.