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ResearchIn-Press PreviewDevelopmentVascular biology Open Access | 10.1172/jci.insight.198032

Beta-arrestin 1/2 are essential for embryonic lymphatic vessel development

Yanna Tian,1 D. Stephen Serafin,1 Monserrat Avila-Zozaya,1 Alyssa M. Tauro,1 Natalie M. Torres-Valle,1 Bryan M. Kistner,1 Danielle M. Dy,1 Elizabeth S. Douglas,1 and Kathleen M. Caron1

1Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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Published March 26, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.198032.
Copyright © 2026, Tian et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published March 26, 2026 - Version history
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Abstract

β-arrestins are ubiquitously expressed cytosolic adaptor proteins that regulate G protein-coupled receptor-dependent and -independent pathways essential for numerous physiological functions. This study investigated the role of β-arrestin1 and -2 in embryonic lymphatic vessel development and survival by generating and characterizing mice with lymphatic, tamoxifen-inducible loss of the genes encoding β-arrestin-1 and -2 (Arrb1/2ΔiLEC). At embryonic day15.5 (E15.5), Arrb1/2ΔiLEC embryos exhibit profound hydrops fetalis and increased embryonic mortality compared to control Arrb1/2fl/fl embryos. Edematous Arrb1/2ΔiLEC embryos, which were more often represented by the female sex, showed growth restriction and decreased lymphatic endothelial cell (LEC) proliferation in the jugular lymphatic sac compared to controls. In vitro knockdown of β-arrestin1 in LECs increased proliferation and increased activation of AKT, while knockdown of β-arrestin2 decreased proliferation and decreased activation of both ERK and CREB. Arrb1/2ΔiLEC embryos also exhibited dilated dermal lymphatics with decreased continuous VE-Cadherin adherens junctions compared to controls. These results were recapitulated in vitro in β-arrestin1 and/or -2 knockdown human LECs, which showed a decrease in membrane VE-Cadherin and β-catenin levels, and prevention of adrenomedullin-induced linearization of VE-cadherin at endothelial cell–cell junctions. Collectively, these results demonstrate that loss of β-arrestin1/2 in lymphatics causes hydrops fetalis, mid-gestational growth arrest and embryonic demise associated with reduced LEC proliferation and disrupted VE-Cadherin adherens junctions.

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