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Reduced intracellular chloride concentration impairs angiogenesis by inhibiting oxidative stress-mediated VEGFR2 activation
- Source :
- Acta Pharmacol Sin
- Publication Year :
- 2019
-
Abstract
- Chloride (Cl(−)) homeostasis is of great significance in cardiovascular system. Serum Cl(−) level is inversely associated with the mortality of patients with heart failure. Considering the importance of angiogenesis in the progress of heart failure, this study aims to investigate whether and how reduced intracellular Cl(−) concentration ([Cl(−)](i)) affects angiogenesis. Human umbilical endothelial cells (HUVECs) were treated with normal Cl(−) medium or low Cl(−) medium. We showed that reduction of [Cl(−)](i) (from 33.2 to 16.18 mM) inhibited HUVEC proliferation, migration, cytoskeleton reorganization, tube formation, and subsequently suppressed angiogenesis under basal condition, and VEGF stimulation or hypoxia treatment. Moreover, VEGF-induced NADPH-mediated reactive oxygen species (ROS) generation and VEGFR2 axis activation were markedly attenuated in low Cl(−) medium. We revealed that lowering [Cl(−)](i) inhibited the expression of the membrane-bound catalytic subunits of NADPH, i.e., p22phox and Nox2, and blunted the translocation of cytosolic regulatory subunits p47phox and p67phox, thereby restricting NADPH oxidase complex formation and activation. Furthermore, reduced [Cl(−)](i) enhanced ROS-associated protein tyrosine phosphatase 1B (PTP1B) activity and increased the interaction of VEGFR2 and PTP1B. Pharmacological inhibition of PTP1B reversed the effect of lowering [Cl(−)](i) on VEGFR2 phosphorylation and angiogenesis. In mouse hind limb ischemia model, blockade of Cl(−) efflux using Cl(−) channel inhibitors DIDS or DCPIB (10 mg/kg, i.m., every other day for 2 weeks) significantly enhanced blood flow recovery and new capillaries formation. In conclusion, decrease of [Cl(−)](i) suppresses angiogenesis via inhibiting oxidase stress-mediated VEGFR2 signaling activation by preventing NADPH oxidase complex formation and promoting VEGFR2/PTP1B association, suggesting that modulation of [Cl(−)](i) may be a novel therapeutic avenue for the treatment of angiogenic dysfunction-associated diseases.
- Subjects :
- 0301 basic medicine
Angiogenesis
Neovascularization, Physiologic
medicine.disease_cause
Article
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Chlorides
NADPH oxidase complex
Cell Movement
Ischemia
medicine
Human Umbilical Vein Endothelial Cells
Animals
Humans
Pharmacology (medical)
Cell Proliferation
Pharmacology
Tube formation
chemistry.chemical_classification
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Reactive oxygen species
biology
NADPH Oxidases
General Medicine
Vascular Endothelial Growth Factor Receptor-2
Cell biology
Hindlimb
Mice, Inbred C57BL
Actin Cytoskeleton
Oxidative Stress
030104 developmental biology
chemistry
DIDS
030220 oncology & carcinogenesis
NADPH Oxidase 2
biology.protein
P22phox
Reactive Oxygen Species
Intracellular
Oxidative stress
Subjects
Details
- ISSN :
- 17457254
- Volume :
- 42
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Acta pharmacologica Sinica
- Accession number :
- edsair.doi.dedup.....4e31b8db4b80349946a0a6c14b5ee813