7-ketocholesterol induces endothelial-mesenchymal transition and promotes fibrosis: implications in neovascular age-related macular degeneration and treatment

Oxidized cholesterols and lipids accumulate in Bruch’s membrane in age-related macular degeneration (AMD). It remains unknown what causal relationship exists between these substances and AMD pathophysiology. We addressed the hypothesis that a prevalent form, 7-ketocholesterol (7KC), promotes choroid...

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Vydané v:	Angiogenesis (London) Ročník 24; číslo 3; s. 583 - 595
Hlavní autori:	Wang, Haibo, Ramshekar, Aniket, Kunz, Eric, Hartnett, M. Elizabeth
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	Dordrecht Springer Netherlands 01.08.2021 Springer Nature B.V
Predmet:	Actin Age Age related diseases Animals Biomedical and Life Sciences Biomedicine Cadherins Cancer Research Cardiology Cell Biology Cell death Cell migration Cell Movement - drug effects Choroid - blood supply Choroid - metabolism Choroid - pathology Choroidal Neovascularization - chemically induced Choroidal Neovascularization - metabolism Choroidal Neovascularization - pathology Collagen Endothelial cells Endothelial Cells - metabolism Endothelial Cells - pathology Eye diseases Fibroblast activation protein Fibrosis Growth factors Ketocholesterols - adverse effects Ketocholesterols - pharmacology Lesions Lipids Macular degeneration Macular Degeneration - chemically induced Macular Degeneration - metabolism Macular Degeneration - pathology Mesenchyme Mice Muscles Oncology Ophthalmology Original Paper Proteins Rac1 protein Smad3 protein Smooth muscle Transforming growth factor-b Vascular endothelial growth factor Vascularization Choroidal endothelial cells Non-responsive (or unresponsive) neovascular AMD Endothelial-mesenchymal transition Macular fibrosis Age-related macular degeneration 7-ketocholesterol
ISSN:	0969-6970, 1573-7209, 1573-7209
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Abstract	Oxidized cholesterols and lipids accumulate in Bruch’s membrane in age-related macular degeneration (AMD). It remains unknown what causal relationship exists between these substances and AMD pathophysiology. We addressed the hypothesis that a prevalent form, 7-ketocholesterol (7KC), promotes choroidal endothelial cell (CEC) migration and macular neovascularization in AMD. Compared to control, 7KC injection caused 40% larger lectin-stained lesions, but 70% larger lesions measured by optical coherence tomography one week after laser-injury. At two weeks, 7KC-injected eyes had 86% larger alpha smooth muscle actin (αSMA)-labeled lesions and more collagen-labeling than control. There was no difference in cell death. 7KC-treated RPE/choroids had increased αSMA but decreased VE-cadherin. Compared to control-treated CECs, 7KC unexpectedly reduced endothelial VE-cadherin, CD31 and VEGFR2 and increased αSMA, fibroblast activation protein (FAP) and transforming growth factor beta (TGFβ). Inhibition of TGFβ receptor-mediated signaling by SB431542 abrogated 7KC-induced loss of endothelial and increase in mesenchymal proteins in association with decreased transcription factor, SMAD3. Knockdown of SMAD3 partially inhibited 7KC-mediated loss of endothelial proteins and increase in αSMA and FAP. Compared to control, 7KC-treatment of CECs increased Rac1GTP and migration, and both were inhibited by the Rac1 inhibitor; however, CECs treated with 7KC had reduced tube formation. These findings suggest that 7KC, which increases in AMD and with age, induces mesenchymal transition in CECs making them invasive and migratory, and causing fibrosis in macular neovascularization. Further studies to interfere with this process may reduce fibrosis and improve responsiveness to anti-VEGF treatment in non-responsive macular neovascularization in AMD.
AbstractList	Oxidized cholesterols and lipids accumulate in Bruch's membrane in age-related macular degeneration (AMD). It remains unknown what causal relationship exists between these substances and AMD pathophysiology. We addressed the hypothesis that a prevalent form, 7-ketocholesterol (7KC), promotes choroidal endothelial cell (CEC) migration and macular neovascularization in AMD. Compared to control, 7KC injection caused 40% larger lectin-stained lesions, but 70% larger lesions measured by optical coherence tomography one week after laser-injury. At two weeks, 7KC-injected eyes had 86% larger alpha smooth muscle actin (αSMA)-labeled lesions and more collagen-labeling than control. There was no difference in cell death. 7KC-treated RPE/choroids had increased αSMA but decreased VE-cadherin. Compared to control-treated CECs, 7KC unexpectedly reduced endothelial VE-cadherin, CD31 and VEGFR2 and increased αSMA, fibroblast activation protein (FAP) and transforming growth factor beta (TGFβ). Inhibition of TGFβ receptor-mediated signaling by SB431542 abrogated 7KC-induced loss of endothelial and increase in mesenchymal proteins in association with decreased transcription factor, SMAD3. Knockdown of SMAD3 partially inhibited 7KC-mediated loss of endothelial proteins and increase in αSMA and FAP. Compared to control, 7KC-treatment of CECs increased Rac1GTP and migration, and both were inhibited by the Rac1 inhibitor; however, CECs treated with 7KC had reduced tube formation. These findings suggest that 7KC, which increases in AMD and with age, induces mesenchymal transition in CECs making them invasive and migratory, and causing fibrosis in macular neovascularization. Further studies to interfere with this process may reduce fibrosis and improve responsiveness to anti-VEGF treatment in non-responsive macular neovascularization in AMD.Oxidized cholesterols and lipids accumulate in Bruch's membrane in age-related macular degeneration (AMD). It remains unknown what causal relationship exists between these substances and AMD pathophysiology. We addressed the hypothesis that a prevalent form, 7-ketocholesterol (7KC), promotes choroidal endothelial cell (CEC) migration and macular neovascularization in AMD. Compared to control, 7KC injection caused 40% larger lectin-stained lesions, but 70% larger lesions measured by optical coherence tomography one week after laser-injury. At two weeks, 7KC-injected eyes had 86% larger alpha smooth muscle actin (αSMA)-labeled lesions and more collagen-labeling than control. There was no difference in cell death. 7KC-treated RPE/choroids had increased αSMA but decreased VE-cadherin. Compared to control-treated CECs, 7KC unexpectedly reduced endothelial VE-cadherin, CD31 and VEGFR2 and increased αSMA, fibroblast activation protein (FAP) and transforming growth factor beta (TGFβ). Inhibition of TGFβ receptor-mediated signaling by SB431542 abrogated 7KC-induced loss of endothelial and increase in mesenchymal proteins in association with decreased transcription factor, SMAD3. Knockdown of SMAD3 partially inhibited 7KC-mediated loss of endothelial proteins and increase in αSMA and FAP. Compared to control, 7KC-treatment of CECs increased Rac1GTP and migration, and both were inhibited by the Rac1 inhibitor; however, CECs treated with 7KC had reduced tube formation. These findings suggest that 7KC, which increases in AMD and with age, induces mesenchymal transition in CECs making them invasive and migratory, and causing fibrosis in macular neovascularization. Further studies to interfere with this process may reduce fibrosis and improve responsiveness to anti-VEGF treatment in non-responsive macular neovascularization in AMD. Oxidized cholesterols and lipids accumulate in Bruch’s membrane in age-related macular degeneration (AMD). It remains unknown what causal relationship exists between these substances and AMD pathophysiology. We addressed the hypothesis that a prevalent form, 7-ketocholesterol (7KC), promotes choroidal endothelial cell (CEC) migration and macular neovascularization in AMD. Compared to control, 7KC injection caused 40% larger lectin-stained lesions, but 70% larger lesions measured by optical coherence tomography one week after laser-injury. At two weeks, 7KC-injected eyes had 86% larger alpha smooth muscle actin (αSMA)-labeled lesions and more collagen-labeling than control. There was no difference in cell death. 7KC-treated RPE/choroids had increased αSMA but decreased VE-cadherin. Compared to control-treated CECs, 7KC unexpectedly reduced endothelial VE-cadherin, CD31 and VEGFR2 and increased αSMA, fibroblast activation protein (FAP) and transforming growth factor beta (TGFβ). Inhibition of TGFβ receptor-mediated signaling by SB431542 abrogated 7KC-induced loss of endothelial and increase in mesenchymal proteins in association with decreased transcription factor, SMAD3. Knockdown of SMAD3 partially inhibited 7KC-mediated loss of endothelial proteins and increase in αSMA and FAP. Compared to control, 7KC-treatment of CECs increased Rac1GTP and migration, and both were inhibited by the Rac1 inhibitor; however, CECs treated with 7KC for 72 hours had reduced tube formation. These findings suggest that 7KC, which increases in AMD and with age, induces mesenchymal transition in CECs making them invasive and migratory, and causing fibrosis in macular neovascularization. Further studies to interfere with this process may reduce fibrosis and improve responses to anti-VEGF treatment in non-responsive macular neovascularization in AMD. Oxidized cholesterols and lipids accumulate in Bruch's membrane in age-related macular degeneration (AMD). It remains unknown what causal relationship exists between these substances and AMD pathophysiology. We addressed the hypothesis that a prevalent form, 7-ketocholesterol (7KC), promotes choroidal endothelial cell (CEC) migration and macular neovascularization in AMD. Compared to control, 7KC injection caused 40% larger lectin-stained lesions, but 70% larger lesions measured by optical coherence tomography one week after laser-injury. At two weeks, 7KC-injected eyes had 86% larger alpha smooth muscle actin (αSMA)-labeled lesions and more collagen-labeling than control. There was no difference in cell death. 7KC-treated RPE/choroids had increased αSMA but decreased VE-cadherin. Compared to control-treated CECs, 7KC unexpectedly reduced endothelial VE-cadherin, CD31 and VEGFR2 and increased αSMA, fibroblast activation protein (FAP) and transforming growth factor beta (TGFβ). Inhibition of TGFβ receptor-mediated signaling by SB431542 abrogated 7KC-induced loss of endothelial and increase in mesenchymal proteins in association with decreased transcription factor, SMAD3. Knockdown of SMAD3 partially inhibited 7KC-mediated loss of endothelial proteins and increase in αSMA and FAP. Compared to control, 7KC-treatment of CECs increased Rac1GTP and migration, and both were inhibited by the Rac1 inhibitor; however, CECs treated with 7KC had reduced tube formation. These findings suggest that 7KC, which increases in AMD and with age, induces mesenchymal transition in CECs making them invasive and migratory, and causing fibrosis in macular neovascularization. Further studies to interfere with this process may reduce fibrosis and improve responsiveness to anti-VEGF treatment in non-responsive macular neovascularization in AMD.
Author	Hartnett, M. Elizabeth Wang, Haibo Ramshekar, Aniket Kunz, Eric
Author_xml	– sequence: 1 givenname: Haibo surname: Wang fullname: Wang, Haibo organization: The John A Moran Eye Center, University of Utah – sequence: 2 givenname: Aniket surname: Ramshekar fullname: Ramshekar, Aniket organization: The John A Moran Eye Center, University of Utah – sequence: 3 givenname: Eric surname: Kunz fullname: Kunz, Eric organization: The John A Moran Eye Center, University of Utah – sequence: 4 givenname: M. Elizabeth orcidid: 0000-0002-7270-5670 surname: Hartnett fullname: Hartnett, M. Elizabeth email: ME.Hartnett@hsc.utah.edu organization: The John A Moran Eye Center, University of Utah
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Keywords	Choroidal endothelial cells Non-responsive (or unresponsive) neovascular AMD Endothelial-mesenchymal transition Macular fibrosis Age-related macular degeneration 7-ketocholesterol
Language	English
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Snippet	Oxidized cholesterols and lipids accumulate in Bruch’s membrane in age-related macular degeneration (AMD). It remains unknown what causal relationship exists... Oxidized cholesterols and lipids accumulate in Bruch's membrane in age-related macular degeneration (AMD). It remains unknown what causal relationship exists...
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SubjectTerms	Actin Age Age related diseases Animals Biomedical and Life Sciences Biomedicine Cadherins Cancer Research Cardiology Cell Biology Cell death Cell migration Cell Movement - drug effects Choroid - blood supply Choroid - metabolism Choroid - pathology Choroidal Neovascularization - chemically induced Choroidal Neovascularization - metabolism Choroidal Neovascularization - pathology Collagen Endothelial cells Endothelial Cells - metabolism Endothelial Cells - pathology Eye diseases Fibroblast activation protein Fibrosis Growth factors Ketocholesterols - adverse effects Ketocholesterols - pharmacology Lesions Lipids Macular degeneration Macular Degeneration - chemically induced Macular Degeneration - metabolism Macular Degeneration - pathology Mesenchyme Mice Muscles Oncology Ophthalmology Original Paper Proteins Rac1 protein Smad3 protein Smooth muscle Transforming growth factor-b Vascular endothelial growth factor Vascularization
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Title	7-ketocholesterol induces endothelial-mesenchymal transition and promotes fibrosis: implications in neovascular age-related macular degeneration and treatment
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