Airway Epithelial Genomic Signatures in Steroid-Resistant COPD; Role for SMAD3 in Vascular Remodeling in Pulmonary Hypertension; Regulation of Lung Endothelial Cell Function by VEGFR3
| Autor: | Vickram Tejwani, Gautam Sikka, Karthik Suresh, Larissa A. Shimoda, Xin Yun |
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| Rok vydání: | 2019 |
| Předmět: |
Pulmonary and Respiratory Medicine
Hypertension Pulmonary Clinical Biochemistry Vascular Remodeling Article Pulmonary Disease Chronic Obstructive medicine Humans Smad3 Protein Molecular Biology Pulmonary Arterial Hypertension COPD Lung business.industry Endothelial Cells Genomics Cell Biology medicine.disease Pulmonary hypertension Steroid resistant Endothelial stem cell medicine.anatomical_structure Cancer research business Airway Function (biology) |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 61:392-394 |
| ISSN: | 1535-4989 1044-1549 |
| 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 (GPCRs), 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 crosstalk exist between these diverse signaling pathways. For example, multifunctional β-arrestin (ARRB) adapter proteins are best known as regulators of GPCR signaling but their role at other receptors and their physiological importance in the setting of vascular disease is 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. Additionally, 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 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 eNOS 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 VEGF receptor regulation and suggests a mechanism for cross-talk between GPCRs 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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