Tumor Necrosis factor–Nelated Apoptosis‐Inducing Ligand (TRAIL) Promotes Angiogenesis and Ischemia‐Induced Neovascularization Via NADPH Oxidase 4 (NOX4) and Nitric Oxide–Dependent Mechanisms
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...
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| Format: | Article |
| Language: | English |
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American Heart Association
2015
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| Online Access: | http://irep.iium.edu.my/62221/ http://irep.iium.edu.my/62221/7/62221_Tumor%20Necrosis%20factor%E2%80%93Nelated%20Apoptosis%E2%80%90Inducing%20Ligand.pdf |
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| author | Di Bartolo, Belinda Ann Peta Cartland, Siân Prado‐Lourenco, Leonel Scott Griffith, Thomas Gentile, Carmine Ravindran, Jayant Md. Azahri, Nor Saadah Thai, Thuan Yeung, Amanda Wing Shee Thomas, Shane Ross Kavurma, Mary Meltem |
| author_facet | Di Bartolo, Belinda Ann Peta Cartland, Siân Prado‐Lourenco, Leonel Scott Griffith, Thomas Gentile, Carmine Ravindran, Jayant Md. Azahri, Nor Saadah Thai, Thuan Yeung, Amanda Wing Shee Thomas, Shane Ross Kavurma, Mary Meltem |
| author_sort | Di Bartolo, Belinda Ann |
| building | IIUM Repository |
| collection | Online Access |
| description | 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 CD31 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 siRNA. Both fibroblast growth factor‐2 and TRAIL significantly increased NADPH oxidase 4 (NOX4) expression. TRAIL‐inducible angiogenic activity in vitro was inhibited with siRNAs targeting NOX4, and consistent with this, NOX4 mRNA was reduced in 3‐day ischemic hindlimbs of Trail−/− mice. Furthermore, TRAIL‐induced proliferation, migration, and tubule formation was blocked by scavenging H2O2, 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 NOX4 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 NOX4 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. |
| first_indexed | 2025-11-14T16:59:02Z |
| format | Article |
| id | iium-62221 |
| institution | International Islamic University Malaysia |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T16:59:02Z |
| publishDate | 2015 |
| publisher | American Heart Association |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | iium-622212022-03-15T01:14:16Z http://irep.iium.edu.my/62221/ Tumor Necrosis factor–Nelated Apoptosis‐Inducing Ligand (TRAIL) Promotes Angiogenesis and Ischemia‐Induced Neovascularization Via NADPH Oxidase 4 (NOX4) and Nitric Oxide–Dependent Mechanisms Di Bartolo, Belinda Ann Peta Cartland, Siân Prado‐Lourenco, Leonel Scott Griffith, Thomas Gentile, Carmine Ravindran, Jayant Md. Azahri, Nor Saadah Thai, Thuan Yeung, Amanda Wing Shee Thomas, Shane Ross Kavurma, Mary Meltem R Medicine (General) 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 CD31 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 siRNA. Both fibroblast growth factor‐2 and TRAIL significantly increased NADPH oxidase 4 (NOX4) expression. TRAIL‐inducible angiogenic activity in vitro was inhibited with siRNAs targeting NOX4, and consistent with this, NOX4 mRNA was reduced in 3‐day ischemic hindlimbs of Trail−/− mice. Furthermore, TRAIL‐induced proliferation, migration, and tubule formation was blocked by scavenging H2O2, 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 NOX4 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 NOX4 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. American Heart Association 2015-11-16 Article PeerReviewed application/pdf en http://irep.iium.edu.my/62221/7/62221_Tumor%20Necrosis%20factor%E2%80%93Nelated%20Apoptosis%E2%80%90Inducing%20Ligand.pdf Di Bartolo, Belinda Ann and Peta Cartland, Siân and Prado‐Lourenco, Leonel and Scott Griffith, Thomas and Gentile, Carmine and Ravindran, Jayant and Md. Azahri, Nor Saadah and Thai, Thuan and Yeung, Amanda Wing Shee and Thomas, Shane Ross and Kavurma, Mary Meltem (2015) Tumor Necrosis factor–Nelated Apoptosis‐Inducing Ligand (TRAIL) Promotes Angiogenesis and Ischemia‐Induced Neovascularization Via NADPH Oxidase 4 (NOX4) and Nitric Oxide–Dependent Mechanisms. Journal of the American Heart Association, 4 (11). E-ISSN 2047-9980 https://www.ahajournals.org/journal/jaha |
| spellingShingle | R Medicine (General) Di Bartolo, Belinda Ann Peta Cartland, Siân Prado‐Lourenco, Leonel Scott Griffith, Thomas Gentile, Carmine Ravindran, Jayant Md. Azahri, Nor Saadah Thai, Thuan Yeung, Amanda Wing Shee Thomas, Shane Ross Kavurma, Mary Meltem Tumor Necrosis factor–Nelated Apoptosis‐Inducing Ligand (TRAIL) Promotes Angiogenesis and Ischemia‐Induced Neovascularization Via NADPH Oxidase 4 (NOX4) and Nitric Oxide–Dependent Mechanisms |
| title | Tumor Necrosis factor–Nelated Apoptosis‐Inducing Ligand (TRAIL) Promotes Angiogenesis and Ischemia‐Induced Neovascularization Via NADPH Oxidase 4 (NOX4) and Nitric Oxide–Dependent Mechanisms |
| title_full | Tumor Necrosis factor–Nelated Apoptosis‐Inducing Ligand (TRAIL) Promotes Angiogenesis and Ischemia‐Induced Neovascularization Via NADPH Oxidase 4 (NOX4) and Nitric Oxide–Dependent Mechanisms |
| title_fullStr | Tumor Necrosis factor–Nelated Apoptosis‐Inducing Ligand (TRAIL) Promotes Angiogenesis and Ischemia‐Induced Neovascularization Via NADPH Oxidase 4 (NOX4) and Nitric Oxide–Dependent Mechanisms |
| title_full_unstemmed | Tumor Necrosis factor–Nelated Apoptosis‐Inducing Ligand (TRAIL) Promotes Angiogenesis and Ischemia‐Induced Neovascularization Via NADPH Oxidase 4 (NOX4) and Nitric Oxide–Dependent Mechanisms |
| title_short | Tumor Necrosis factor–Nelated Apoptosis‐Inducing Ligand (TRAIL) Promotes Angiogenesis and Ischemia‐Induced Neovascularization Via NADPH Oxidase 4 (NOX4) and Nitric Oxide–Dependent Mechanisms |
| title_sort | tumor necrosis factor–nelated apoptosis‐inducing ligand (trail) promotes angiogenesis and ischemia‐induced neovascularization via nadph oxidase 4 (nox4) and nitric oxide–dependent mechanisms |
| topic | R Medicine (General) |
| url | http://irep.iium.edu.my/62221/ http://irep.iium.edu.my/62221/ http://irep.iium.edu.my/62221/7/62221_Tumor%20Necrosis%20factor%E2%80%93Nelated%20Apoptosis%E2%80%90Inducing%20Ligand.pdf |