Journal
CIRCULATION
Volume 139, Issue 13, Pages 1629-1642Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.118.034961
Keywords
beta-arrestins; GTP-binding proteins; hypertension, pulmonary; receptors, vascular endothelial growth factor
Funding
- National Institutes of Health (NIH) [HL114643, HL139946]
- Burroughs Wellcome Career Award Medical Scientists
- American Heart Association [GRNT33670458]
- Duke Center for In Vivo Microscopy, an NIH/National Institute of Biomedical Imaging and Bio-engineering National Biomedical Technology Resource Center [P41 EB015897]
- NIH [R01 CA196667, U24 CA220245]
- NIH National Institute of Diabetes, Digestive and Kidney Diseases [P30DK096493]
- Edna and Fred L. Mandel Jr. Foundation for Hypertension and Atherosclerosis at Duke
- NHLBI R24 grant [R24HL123767]
- Cardiovascular Medical Research and Education Fund
- [HL60917]
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BACKGROUND: Receptor signaling is central to vascular endothelial function and is dysregulated in vascular diseases such as atherosclerosis and pulmonary arterial hypertension (PAH). Signaling pathways involved in endothelial function include vascular endothelial growth factor receptors (VEGFRs) and G protein-coupled receptors, which classically activate distinct intracellular signaling pathways and responses. The mechanisms that regulate these signaling pathways have not been fully elucidated and it is unclear what nodes for cross talk exist between these diverse signaling pathways. For example, multifunctional beta-arrestin (ARRB) adapter proteins are best known as regulators of G protein-coupled receptor signaling, but their role at other receptors and their physiological importance in the setting of vascular disease are unclear. METHODS: We used a combination of human samples from PAH, human microvascular endothelial cells from lung, and Arrb knockout mice to determine the role of ARRB1 in endothelial VEGFR3 signaling. In addition, a number of biochemical analyses were performed to determine the interaction between ARRB1 and VEGFR3, signaling mediators downstream of VEGFR3, and the internalization of VEGFR3. RESULTS: Expression of ARRB1 and VEGFR3 was reduced in human PAH, and the deletion of Arrb1 in mice exposed to hypoxia led to worse PAH with a loss of VEGFR3 signaling. Knockdown of ARRB1 inhibited VEGF-C-induced endothelial cell proliferation, migration, and tube formation, along with reduced VEGFR3, Akt, and endothelial nitric oxide synthase phosphorylation. This regulation was mediated by direct ARRB1 binding to the VEGFR3 kinase domain and resulted in decreased VEGFR3 internalization. CONCLUSIONS: Our results demonstrate a novel role for ARRB1 in VEGFR regulation and suggest a mechanism for cross talk between G protein-coupled receptors and VEGFRs in PAH. These findings also suggest that strategies to promote ARRB1-mediated VEGFR3 signaling could be useful in the treatment of pulmonary hypertension and other vascular disease.
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