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Critical role of caveolin-1 in ocular neovascularization and multitargeted antiangiogenic effects of cavtratin via JNK.
journal contribution
posted on 2019-08-29, 15:30 authored by Y Jiang, X Lin, Z Tang, C Lee, G Tian, Y Du, X Yin, X Ren, L Huang, Z Ye, W Chen, F Zhang, J Mi, Z Gao, S Wang, Q Chen, L Xing, B Wang, Y Cao, WC Sessa, R Ju, Y Liu, X LiOcular neovascularization is a devastating pathology of numerous ocular diseases and is a major cause of blindness. Caveolin-1 (Cav-1) plays important roles in the vascular system. However, little is known regarding its function and mechanisms in ocular neovascularization. Here, using comprehensive model systems and a cell permeable peptide of Cav-1, cavtratin, we show that Cav-1 is a critical player in ocular neovascularization. The genetic deletion of Cav-1 exacerbated and cavtratin administration inhibited choroidal and retinal neovascularization. Importantly, combined administration of cavtratin and anti-VEGF-A inhibited neovascularization more effectively than monotherapy, suggesting the existence of other pathways inhibited by cavtratin in addition to VEGF-A. Indeed, we found that cavtratin suppressed multiple critical components of pathological angiogenesis, including inflammation, permeability, PDGF-B and endothelial nitric oxide synthase expression (eNOS). Mechanistically, we show that cavtratin inhibits CNV and the survival and migration of microglia and macrophages via JNK. Together, our data demonstrate the unique advantages of cavtratin in antiangiogenic therapy to treat neovascular diseases.
Ocular neovascularization is a devastating pathology of numerous ocular diseases and is a major cause of blindness. Caveolin-1 (Cav-1) plays important roles in the vascular system. However, little is known regarding its function and mechanisms in ocular neovascularization. Here, using comprehensive model systems and a cell permeable peptide of Cav-1, cavtratin, we show that Cav-1 is a critical player in ocular neovascularization. The genetic deletion of Cav-1 exacerbated and cavtratin administration inhibited choroidal and retinal neovascularization. Importantly, combined administration of cavtratin and anti–VEGF-A inhibited neovascularization more effectively than monotherapy, suggesting the existence of other pathways inhibited by cavtratin in addition to VEGF-A. Indeed, we found that cavtratin suppressed multiple critical components of pathological angiogenesis, including inflammation, permeability, PDGF-B and endothelial nitric oxide synthase expression (eNOS). Mechanistically, we show that cavtratin inhibits CNV and the survival and migration of microglia and macrophages via JNK. Together, our data demonstrate the unique advantages of cavtratin in antiangiogenic therapy to treat neovascular diseases.
Funding
This research was supported by the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University (Guangzhou, People’s Republic of China); a Taishan Scholar’s program (X. Li and B.W.); a key program of the National Natural Science Foundation of China (NSFC) (Grant 81330021 to X. Li); NSFC Grant 81670855 (to X. Li); NSFC–Swedish Research Foundation International Collaboration Grant 81611130082 (to X. Li); Guangdong Province Leading Expert Program (X. Li); and NSFC Grant 81470644 (to R.J.).
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Citation
Proceedings of the National Academy of Science USA, 114 (40), pp. 10737-10742Author affiliation
/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cardiovascular SciencesPublished in
Proceedings of the National Academy of Science USAeissn
1091-6490Acceptance date
2017-08-16Copyright date
2017Available date
2019-08-29Publisher DOI
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engAdministrator link
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Keywords
angiogenesiscaveolin-1cavtratininflammationocular neovascularizationAngiogenesis InhibitorsAnimalsAntibodies, MonoclonalCaveolin 1Choroidal NeovascularizationDrug Therapy, CombinationHumansMAP Kinase Kinase 4Mice, KnockoutPeptide FragmentsRetinal NeovascularizationVascular Endothelial Growth Factor A
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