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Abstract
β-Arrestins are ubiquitously expressed cytosolic adaptor proteins that regulate GPCR-dependent and -independent pathways essential for numerous physiological functions. This study investigated the role of β-arrestin1/2 in embryonic lymphatic vessel development and survival by generating and characterizing mice with lymphatic tamoxifen-inducible loss of the genes encoding β-arrestin1/2 (Arrb1/2ΔiLEC). At E15.5, Arrb1/2ΔiLEC embryos exhibited profound hydrops fetalis and increased embryonic mortality compared with 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 with 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 with controls. These results were recapitulated in vitro in β-arrestin1/2 knockdown human LECs, which showed a decrease in membrane VE-cadherin and β-catenin levels, in addition to 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, midgestational growth arrest, and embryonic demise associated with reduced LEC proliferation and disrupted VE-cadherin adherens junctions.
Authors
Yanna Tian, D. Stephen Serafin, Monserrat Avila-Zozaya, Alyssa M. Tauro, Natalie M. Torres-Valle, Bryan M. Kistner, Danielle M. Dy, Elizabeth S. Douglas, Kathleen M. Caron
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