Vascular Endothelial Growth Factor Receptor 3 Regulates Endothelial Function Through β-Arrestin 1

Area of Science:

• Vascular Biology
• Molecular Signaling
• Cardiovascular Research

Background:

• Endothelial function relies on receptor signaling, often dysregulated in vascular diseases like pulmonary arterial hypertension (PAH).
• Vascular endothelial growth factor receptors (VEGFRs) and G protein-coupled receptors classically activate distinct pathways, with limited understanding of their cross-talk mechanisms.
• The role of beta-arrestin (ARRB) proteins, primarily known for G protein-coupled receptor regulation, in other receptor systems and vascular disease remains unclear.

Purpose of the Study:

• To investigate the role of beta-arrestin 1 (ARRB1) in endothelial vascular endothelial growth factor receptor 3 (VEGFR3) signaling.
• To elucidate the mechanisms of ARRB1 interaction with VEGFR3 and its downstream signaling in the context of vascular disease.

Main Methods:

• Utilized human PAH samples, human lung microvascular endothelial cells, and Arrb knockout mice.
• Performed biochemical analyses to assess ARRB1-VEGFR3 interaction, downstream signaling, and VEGFR3 internalization.
• Investigated the impact of ARRB1 deletion/knockdown on endothelial cell function and PAH development.

Main Results:

• ARRB1 and VEGFR3 expression were reduced in human PAH samples.
• Arrb1 deletion in mice worsened hypoxia-induced PAH, correlating with lost VEGFR3 signaling.
• ARRB1 knockdown inhibited VEGF-C-induced endothelial cell proliferation, migration, and tube formation, with reduced VEGFR3, Akt, and eNOS phosphorylation.
• ARRB1 directly binds to the VEGFR3 kinase domain, decreasing VEGFR3 internalization.

Conclusions:

• Demonstrated a novel role for ARRB1 in regulating VEGFR3 signaling.
• Identified a mechanism for cross-talk between G protein-coupled receptors and VEGFRs in PAH.
• Suggests that enhancing ARRB1-mediated VEGFR3 signaling could be a therapeutic strategy for pulmonary hypertension and other vascular diseases.