Tumor Necrosis Factor–Related Apoptosis‐Inducing Ligand (TRAIL) Promotes Angiogenesis and Ischemia‐Induced Neovascularization Via NADPH Oxidase 4 (NOX4) and Nitric Oxide–Dependent Mechanisms

Autor: Thomas S. Griffith, Carmine Gentile, Mary M. Kavurma, Jayant Ravindran, Amanda W. S. Yeung, Shane R. Thomas, Nor Saadah Muhammad Azahri, Belinda A. Di Bartolo, Thuan Thai, Siân P. Cartland, Leonel Prado-Lourenco
Rok vydání: 2015
Předmět:
CD31
Time Factors
Angiogenesis
Apoptosis
TNF-Related Apoptosis-Inducing Ligand
Neovascularization
angiogenesis
chemistry.chemical_compound
Cell Movement
Medicine
Phosphorylation
Cells
Cultured
Original Research
Mice
Knockout
biology
NOX4
Nitric Oxide Synthase Type III
Hindlimb
Platelet Endothelial Cell Adhesion Molecule-1
Endothelial stem cell
Nitric oxide synthase
Phenotype
NADPH Oxidase 4
endothelial cell
Female
RNA Interference
medicine.symptom
Cardiology and Cardiovascular Medicine
Signal Transduction
Genotype
Neovascularization
Physiologic
ischemia
Nitric Oxide
Transfection
Nitric oxide
Animals
Humans
Muscle
Skeletal
Ultrasonography
Interventional
Cell Proliferation
business.industry
NADPH Oxidases
Capillaries
Mice
Inbred C57BL
Disease Models
Animal
chemistry
Immunology
gene expression
biology.protein
Cancer research
business
Biomarkers
Zdroj: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
ISSN: 2047-9980
DOI: 10.1161/jaha.115.002527
Popis: Background Tumor necrosis factor–related apoptosis‐inducing ligand ( TRAIL ) has the ability to inhibit angiogenesis by inducing endothelial cell death, as well as being able to promote pro‐angiogenic activity in vitro. These seemingly opposite effects make its role in ischemic disease unclear. Using Trail −/− and wildtype mice, we sought to determine the role of TRAIL in angiogenesis and neovascularization following hindlimb ischemia. Methods and Results Reduced vascularization assessed by real‐time 3‐dimensional Vevo ultrasound imaging and CD 31 staining was evident in Trail −/− mice after ischemia, and associated with reduced capillary formation and increased apoptosis. Notably, adenoviral TRAIL administration significantly improved limb perfusion, capillary density, and vascular smooth‐muscle cell content in both Trail −/− and wildtype mice. Fibroblast growth factor‐2, a potent angiogenic factor, increased TRAIL expression in human microvascular endothelial cell‐1, with fibroblast growth factor‐2‐mediated proliferation, migration, and tubule formation inhibited with TRAIL si RNA . Both fibroblast growth factor‐2 and TRAIL significantly increased NADPH oxidase 4 ( NOX 4) expression. TRAIL ‐inducible angiogenic activity in vitro was inhibited with si RNA s targeting NOX 4, and consistent with this, NOX 4 mRNA was reduced in 3‐day ischemic hindlimbs of Trail −/− mice. Furthermore, TRAIL ‐induced proliferation, migration, and tubule formation was blocked by scavenging H 2 O 2 , or by inhibiting nitric oxide synthase activity. Importantly, TRAIL ‐inducible endothelial nitric oxide synthase phosphorylation at Ser‐1177 and intracellular human microvascular endothelial cell‐1 cell nitric oxide levels were NOX 4 dependent. Conclusions This is the first report demonstrating that TRAIL can promote angiogenesis following hindlimb ischemia in vivo. The angiogenic effect of TRAIL on human microvascular endothelial cell‐1 cells is downstream of fibroblast growth factor‐2, involving NOX 4 and nitric oxide signaling. These data have significant therapeutic implications, such that TRAIL may improve the angiogenic response to ischemia and increase perfusion recovery in patients with cardiovascular disease and diabetes.
Databáze: OpenAIRE
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