Disruption of Swell1/VRAC function impairs initial hemodynamics and activates compensatory leukotriene signaling in zebrafish circulation development
Year: 2025
Type: article
Abstract: Background 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. Results 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. Conclusion 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.
Institutions: National Taiwan University, Taipei Medical University
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
Awards: The Role of Volume-Sensitive Organic Osmolyte-Anion Channel in the Immune and Lymphocyte Homeostasis, Elucidating the Gene-Regulatory Network Governing Cholesterol Homeodynamics Using Genome-Edited Mutant Zebrafish Model, G7090632280, G7274079605, G8680862188, G872899017, G8887349171, G8911109390
OpenAlex ID: W4417449204