Role of β-arrestin1/2 in embryonic lymphatic vessel development and maintenance

Lymphatic dysfunction can lead to fetal loss due to interstitial edema known as hydrops fetalis during development and lymphedema in adulthood. Lymphedema affects an estimated 250 million individuals worldwide, yet there is no effective treatment available. Numerous studies have established G protein-coupled receptors (GPCRs) as key lymphangiogenic signaling pathways and ideal druggable therapeutic targets. β-arrestins (β-arrestin 1 and 2) are ubiquitously expressed cytosolic adaptor proteins which perform a wide range of functions in GPCR pathways, such as promoting agonist-induced internalization and forming signaling scaffolds with internalized GPCRs in endosomes. However, the roles of β-arrestins in lymphatic vessel development and function remain undefined. We hypothesize that β-arrestin1/2 are essential in embryonic lymphatic vessel development and maintenance. To test this hypothesis, I investigated the role of β-arrestin-1 and -2 in embryonic lymphatic vessel development using a tamoxifen-inducible, lymphatic-specific β-arrestin-1 and -2 (Arrb1/2 fl/fl); Prox1 CreERT2 (Arrb1/2DiLEC) mouse line. Compared to Arrb1/2fl/fl embryos, the Arrb1/2DiLEC embryos exhibit profound hydrops fetalis and increased embryonic lethality between E14.5 and E17.5. At E15.5, the Arrb1/2DiLEC with edema embryos exhibit reduced weight, enlarged jugular lymphatic sacs, and dilated dermal lymphatic vessels with decreased continuous button junctions in the Arrb1/2DiLEC embryos compared with controls. Mechanistically, knockdown of ARRB1 in the Human Dermal Lymphatic Endothelial Cells (LECs) causes increased cell proliferation through activation of AKT, while knockdown of ARRB2 decreases proliferation with a decrease in both ERK and CREB activation. β-arrestin1 and/or -2 knockdown in human LECs decreased membrane VE-Cadherin and β-catenin levels. Collectively, our results demonstrate that loss of β-arrestin1/2 expression in lymphatics causes embryonic mid-gestational arrest and fetal growth restriction, and dilated lymphatic vessels, with disrupted LEC proliferation and VE-Cadherin adherens junctions. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.