Cargando…
PAI-1 is a vascular cell–specific HIF-2–dependent angiogenic factor that promotes retinal neovascularization in diabetic patients
For patients with proliferative diabetic retinopathy (PDR) who do not respond adequately to pan-retinal laser photocoagulation (PRP) or anti–vascular endothelial growth factor (VEGF) therapies, we hypothesized that vascular cells within neovascular tissue secrete autocrine/paracrine angiogenic facto...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8890718/ https://www.ncbi.nlm.nih.gov/pubmed/35235351 http://dx.doi.org/10.1126/sciadv.abm1896 |
_version_ | 1784661703986774016 |
---|---|
author | Qin, Yaowu Zhang, Jing Babapoor-Farrokhran, Savalan Applewhite, Brooks Deshpande, Monika Megarity, Haley Flores-Bellver, Miguel Aparicio-Domingo, Silvia Ma, Tao Rui, Yuan Tzeng, Stephany Y. Green, Jordan J. Canto-Soler, M. Valeria Montaner, Silvia Sodhi, Akrit |
author_facet | Qin, Yaowu Zhang, Jing Babapoor-Farrokhran, Savalan Applewhite, Brooks Deshpande, Monika Megarity, Haley Flores-Bellver, Miguel Aparicio-Domingo, Silvia Ma, Tao Rui, Yuan Tzeng, Stephany Y. Green, Jordan J. Canto-Soler, M. Valeria Montaner, Silvia Sodhi, Akrit |
author_sort | Qin, Yaowu |
collection | PubMed |
description | For patients with proliferative diabetic retinopathy (PDR) who do not respond adequately to pan-retinal laser photocoagulation (PRP) or anti–vascular endothelial growth factor (VEGF) therapies, we hypothesized that vascular cells within neovascular tissue secrete autocrine/paracrine angiogenic factors that promote disease progression. To identify these factors, we performed multiplex ELISA angiogenesis arrays on aqueous fluid from PDR patients who responded inadequately to anti-VEGF therapy and/or PRP and identified plasminogen activator inhibitor-1 (PAI-1). PAI-1 expression was increased in vitreous biopsies and neovascular tissue from PDR eyes, limited to retinal vascular cells, regulated by the transcription factor hypoxia-inducible factor (HIF)-2α, and necessary and sufficient to stimulate angiogenesis. Using a pharmacologic inhibitor of HIF-2α (PT-2385) or nanoparticle-mediated RNA interference targeting Pai1, we demonstrate that the HIF-2α/PAI-1 axis is necessary for the development of retinal neovascularization in mice. These results suggest that targeting HIF-2α/PAI-1 will be an effective adjunct therapy for the treatment of PDR patients. |
format | Online Article Text |
id | pubmed-8890718 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-88907182022-03-14 PAI-1 is a vascular cell–specific HIF-2–dependent angiogenic factor that promotes retinal neovascularization in diabetic patients Qin, Yaowu Zhang, Jing Babapoor-Farrokhran, Savalan Applewhite, Brooks Deshpande, Monika Megarity, Haley Flores-Bellver, Miguel Aparicio-Domingo, Silvia Ma, Tao Rui, Yuan Tzeng, Stephany Y. Green, Jordan J. Canto-Soler, M. Valeria Montaner, Silvia Sodhi, Akrit Sci Adv Biomedicine and Life Sciences For patients with proliferative diabetic retinopathy (PDR) who do not respond adequately to pan-retinal laser photocoagulation (PRP) or anti–vascular endothelial growth factor (VEGF) therapies, we hypothesized that vascular cells within neovascular tissue secrete autocrine/paracrine angiogenic factors that promote disease progression. To identify these factors, we performed multiplex ELISA angiogenesis arrays on aqueous fluid from PDR patients who responded inadequately to anti-VEGF therapy and/or PRP and identified plasminogen activator inhibitor-1 (PAI-1). PAI-1 expression was increased in vitreous biopsies and neovascular tissue from PDR eyes, limited to retinal vascular cells, regulated by the transcription factor hypoxia-inducible factor (HIF)-2α, and necessary and sufficient to stimulate angiogenesis. Using a pharmacologic inhibitor of HIF-2α (PT-2385) or nanoparticle-mediated RNA interference targeting Pai1, we demonstrate that the HIF-2α/PAI-1 axis is necessary for the development of retinal neovascularization in mice. These results suggest that targeting HIF-2α/PAI-1 will be an effective adjunct therapy for the treatment of PDR patients. American Association for the Advancement of Science 2022-03-02 /pmc/articles/PMC8890718/ /pubmed/35235351 http://dx.doi.org/10.1126/sciadv.abm1896 Text en Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences Qin, Yaowu Zhang, Jing Babapoor-Farrokhran, Savalan Applewhite, Brooks Deshpande, Monika Megarity, Haley Flores-Bellver, Miguel Aparicio-Domingo, Silvia Ma, Tao Rui, Yuan Tzeng, Stephany Y. Green, Jordan J. Canto-Soler, M. Valeria Montaner, Silvia Sodhi, Akrit PAI-1 is a vascular cell–specific HIF-2–dependent angiogenic factor that promotes retinal neovascularization in diabetic patients |
title | PAI-1 is a vascular cell–specific HIF-2–dependent angiogenic factor that promotes retinal neovascularization in diabetic patients |
title_full | PAI-1 is a vascular cell–specific HIF-2–dependent angiogenic factor that promotes retinal neovascularization in diabetic patients |
title_fullStr | PAI-1 is a vascular cell–specific HIF-2–dependent angiogenic factor that promotes retinal neovascularization in diabetic patients |
title_full_unstemmed | PAI-1 is a vascular cell–specific HIF-2–dependent angiogenic factor that promotes retinal neovascularization in diabetic patients |
title_short | PAI-1 is a vascular cell–specific HIF-2–dependent angiogenic factor that promotes retinal neovascularization in diabetic patients |
title_sort | pai-1 is a vascular cell–specific hif-2–dependent angiogenic factor that promotes retinal neovascularization in diabetic patients |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8890718/ https://www.ncbi.nlm.nih.gov/pubmed/35235351 http://dx.doi.org/10.1126/sciadv.abm1896 |
work_keys_str_mv | AT qinyaowu pai1isavascularcellspecifichif2dependentangiogenicfactorthatpromotesretinalneovascularizationindiabeticpatients AT zhangjing pai1isavascularcellspecifichif2dependentangiogenicfactorthatpromotesretinalneovascularizationindiabeticpatients AT babapoorfarrokhransavalan pai1isavascularcellspecifichif2dependentangiogenicfactorthatpromotesretinalneovascularizationindiabeticpatients AT applewhitebrooks pai1isavascularcellspecifichif2dependentangiogenicfactorthatpromotesretinalneovascularizationindiabeticpatients AT deshpandemonika pai1isavascularcellspecifichif2dependentangiogenicfactorthatpromotesretinalneovascularizationindiabeticpatients AT megarityhaley pai1isavascularcellspecifichif2dependentangiogenicfactorthatpromotesretinalneovascularizationindiabeticpatients AT floresbellvermiguel pai1isavascularcellspecifichif2dependentangiogenicfactorthatpromotesretinalneovascularizationindiabeticpatients AT apariciodomingosilvia pai1isavascularcellspecifichif2dependentangiogenicfactorthatpromotesretinalneovascularizationindiabeticpatients AT matao pai1isavascularcellspecifichif2dependentangiogenicfactorthatpromotesretinalneovascularizationindiabeticpatients AT ruiyuan pai1isavascularcellspecifichif2dependentangiogenicfactorthatpromotesretinalneovascularizationindiabeticpatients AT tzengstephanyy pai1isavascularcellspecifichif2dependentangiogenicfactorthatpromotesretinalneovascularizationindiabeticpatients AT greenjordanj pai1isavascularcellspecifichif2dependentangiogenicfactorthatpromotesretinalneovascularizationindiabeticpatients AT cantosolermvaleria pai1isavascularcellspecifichif2dependentangiogenicfactorthatpromotesretinalneovascularizationindiabeticpatients AT montanersilvia pai1isavascularcellspecifichif2dependentangiogenicfactorthatpromotesretinalneovascularizationindiabeticpatients AT sodhiakrit pai1isavascularcellspecifichif2dependentangiogenicfactorthatpromotesretinalneovascularizationindiabeticpatients |