Vascular Endothelial Growth Factor Receptor 3 Regulates Endothelial Function Through β-Arrestin 1
| Autor: | Jeffrey J. Kovacs, Zhiyuan Ma, Cristian T. Badea, Claude A. Piantadosi, Xinyu Xiong, Sudarshan Rajagopal, Suzy Comhair, Yen-Rei A. Yu |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Hypertension Pulmonary Vascular Endothelial Growth Factor Receptor Mice 03 medical and health sciences 0302 clinical medicine GTP-binding protein regulators Physiology (medical) medicine Animals Humans 030304 developmental biology G protein-coupled receptor Mice Knockout 0303 health sciences Beta-Arrestins business.industry Vascular Endothelial Growth Factor Receptor-3 Reading Beyond the Red: What Fellows are Reading in Other Journals medicine.disease Pulmonary hypertension Cell biology beta-Arrestin 1 030220 oncology & carcinogenesis β arrestin 1 Arrestin beta 2 Endothelium Vascular Cardiology and Cardiovascular Medicine business Function (biology) Signal Transduction |
| Zdroj: | Am J Respir Cell Mol Biol |
| ISSN: | 1524-4539 0009-7322 |
| DOI: | 10.1161/circulationaha.118.034961 |
| Popis: | 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 β-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. |
| Databáze: | OpenAIRE |
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