Activator of G-protein signaling 8 is involved in VEGF-induced choroidal neovascularization

Choroidal neovascularization (CNV) is associated with age-related macular degeneration (AMD), a major cause of vision loss among elderly people. Vascular endothelial cell growth factor (VEGF) is essential for the development and progression of AMD, and VEGF signaling molecules are effective targets...

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Veröffentlicht in:Scientific reports 2019-02, Vol.9 (1), p.1560, Article 1560
Hauptverfasser: Hayashi, Hisaki, Mamun, Abdullah Al, Takeyama, Masayuki, Yamamura, Aya, Zako, Masahiro, Yagasaki, Rina, Nakahara, Tsutomu, Kamei, Motohiro, Sato, Motohiko
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container_title Scientific reports
container_volume 9
creator Hayashi, Hisaki
Mamun, Abdullah Al
Takeyama, Masayuki
Yamamura, Aya
Zako, Masahiro
Yagasaki, Rina
Nakahara, Tsutomu
Kamei, Motohiro
Sato, Motohiko
description Choroidal neovascularization (CNV) is associated with age-related macular degeneration (AMD), a major cause of vision loss among elderly people. Vascular endothelial cell growth factor (VEGF) is essential for the development and progression of AMD, and VEGF signaling molecules are effective targets for the treatment of AMD. We recently reported that activator of G-protein signaling 8 (AGS8), a receptor-independent Gβγ regulator, is involved in VEGF-induced angiogenesis in cultured endothelial cells (EC); however, the role of AGS8 in CNV is not yet understood. This study aimed to explore the role of AGS8 in CNV in cultured cells, explanted choroid tissue, and laser-induced CNV in a mouse AMD model. AGS8 knockdown in cultured choroidal EC inhibited VEGF-induced VEGFR-2 phosphorylation, cell proliferation, and migration. AGS8 knockdown also downregulated cell sprouting from mouse choroidal tissue in ex vivo culture. A mouse model of laser-induced CNV, created to analyze the roles of AGS8 in vivo , demonstrated that AGS8 mRNA was significantly upregulated in choroidal lesions and AGS8 was specifically expressed in the neovasculature. Local AGS8 knockdown in intravitreal tissue significantly inhibited laser-induced AGS8 upregulation and suppressed CNV, suggesting that AGS8 knockdown in the choroid has therapeutic potential for AMD. Together, these results demonstrate that AGS8 plays critical roles in VEGF-induced CNV.
doi_str_mv 10.1038/s41598-018-38067-4
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Vascular endothelial cell growth factor (VEGF) is essential for the development and progression of AMD, and VEGF signaling molecules are effective targets for the treatment of AMD. We recently reported that activator of G-protein signaling 8 (AGS8), a receptor-independent Gβγ regulator, is involved in VEGF-induced angiogenesis in cultured endothelial cells (EC); however, the role of AGS8 in CNV is not yet understood. This study aimed to explore the role of AGS8 in CNV in cultured cells, explanted choroid tissue, and laser-induced CNV in a mouse AMD model. AGS8 knockdown in cultured choroidal EC inhibited VEGF-induced VEGFR-2 phosphorylation, cell proliferation, and migration. AGS8 knockdown also downregulated cell sprouting from mouse choroidal tissue in ex vivo culture. A mouse model of laser-induced CNV, created to analyze the roles of AGS8 in vivo , demonstrated that AGS8 mRNA was significantly upregulated in choroidal lesions and AGS8 was specifically expressed in the neovasculature. Local AGS8 knockdown in intravitreal tissue significantly inhibited laser-induced AGS8 upregulation and suppressed CNV, suggesting that AGS8 knockdown in the choroid has therapeutic potential for AMD. Together, these results demonstrate that AGS8 plays critical roles in VEGF-induced CNV.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-018-38067-4</identifier><identifier>PMID: 30733465</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/106 ; 13/31 ; 13/95 ; 14/63 ; 38/90 ; 42/89 ; 631/443/7 ; 631/80/86 ; 64/60 ; 82/51 ; Age ; Angiogenesis ; Animals ; Cell culture ; Cell growth ; Cell Line ; Cell migration ; Cell proliferation ; Cells, Cultured ; Choroidal Neovascularization - etiology ; Choroidal Neovascularization - metabolism ; Choroidal Neovascularization - pathology ; Disease Models, Animal ; Disease Susceptibility ; Endothelial cells ; Endothelial Cells - metabolism ; Gene Expression ; Geriatrics ; Humanities and Social Sciences ; Intracellular Signaling Peptides and Proteins - genetics ; Intracellular Signaling Peptides and Proteins - metabolism ; Lasers ; Macaca mulatta ; Macular degeneration ; Macular Degeneration - etiology ; Macular Degeneration - metabolism ; Macular Degeneration - pathology ; Male ; Mice ; mRNA ; multidisciplinary ; Phosphorylation ; RNA, Small Interfering - genetics ; Science ; Science (multidisciplinary) ; Tissue culture ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factor A - genetics ; Vascular Endothelial Growth Factor A - metabolism ; Vascular endothelial growth factor receptors ; Vascularization</subject><ispartof>Scientific reports, 2019-02, Vol.9 (1), p.1560, Article 1560</ispartof><rights>The Author(s) 2019</rights><rights>This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). 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A mouse model of laser-induced CNV, created to analyze the roles of AGS8 in vivo , demonstrated that AGS8 mRNA was significantly upregulated in choroidal lesions and AGS8 was specifically expressed in the neovasculature. Local AGS8 knockdown in intravitreal tissue significantly inhibited laser-induced AGS8 upregulation and suppressed CNV, suggesting that AGS8 knockdown in the choroid has therapeutic potential for AMD. 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Vascular endothelial cell growth factor (VEGF) is essential for the development and progression of AMD, and VEGF signaling molecules are effective targets for the treatment of AMD. We recently reported that activator of G-protein signaling 8 (AGS8), a receptor-independent Gβγ regulator, is involved in VEGF-induced angiogenesis in cultured endothelial cells (EC); however, the role of AGS8 in CNV is not yet understood. This study aimed to explore the role of AGS8 in CNV in cultured cells, explanted choroid tissue, and laser-induced CNV in a mouse AMD model. AGS8 knockdown in cultured choroidal EC inhibited VEGF-induced VEGFR-2 phosphorylation, cell proliferation, and migration. AGS8 knockdown also downregulated cell sprouting from mouse choroidal tissue in ex vivo culture. A mouse model of laser-induced CNV, created to analyze the roles of AGS8 in vivo , demonstrated that AGS8 mRNA was significantly upregulated in choroidal lesions and AGS8 was specifically expressed in the neovasculature. Local AGS8 knockdown in intravitreal tissue significantly inhibited laser-induced AGS8 upregulation and suppressed CNV, suggesting that AGS8 knockdown in the choroid has therapeutic potential for AMD. Together, these results demonstrate that AGS8 plays critical roles in VEGF-induced CNV.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>30733465</pmid><doi>10.1038/s41598-018-38067-4</doi><oa>free_for_read</oa></addata></record>
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subjects 13
13/106
13/31
13/95
14/63
38/90
42/89
631/443/7
631/80/86
64/60
82/51
Age
Angiogenesis
Animals
Cell culture
Cell growth
Cell Line
Cell migration
Cell proliferation
Cells, Cultured
Choroidal Neovascularization - etiology
Choroidal Neovascularization - metabolism
Choroidal Neovascularization - pathology
Disease Models, Animal
Disease Susceptibility
Endothelial cells
Endothelial Cells - metabolism
Gene Expression
Geriatrics
Humanities and Social Sciences
Intracellular Signaling Peptides and Proteins - genetics
Intracellular Signaling Peptides and Proteins - metabolism
Lasers
Macaca mulatta
Macular degeneration
Macular Degeneration - etiology
Macular Degeneration - metabolism
Macular Degeneration - pathology
Male
Mice
mRNA
multidisciplinary
Phosphorylation
RNA, Small Interfering - genetics
Science
Science (multidisciplinary)
Tissue culture
Vascular endothelial growth factor
Vascular Endothelial Growth Factor A - genetics
Vascular Endothelial Growth Factor A - metabolism
Vascular endothelial growth factor receptors
Vascularization
title Activator of G-protein signaling 8 is involved in VEGF-induced choroidal neovascularization
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