Therapeutic activation of endothelial sphingosine‐1‐phosphate receptor 1 by chaperone‐bound S1P suppresses proliferative retinal neovascularization
Abstract Sphingosine‐1‐phosphate (S1P), the circulating HDL‐bound lipid mediator that acts via S1P receptors (S1PR), is required for normal vascular development. The role of this signaling axis in vascular retinopathies is unclear. Here, we show in a mouse model of oxygen‐induced retinopathy (OIR) t...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2023-03-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202216645 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849234797861273600 |
|---|---|
| author | Colin Niaudet Bongnam Jung Andrew Kuo Steven Swendeman Edward Bull Takahiro Seno Reed Crocker Zhongjie Fu Lois E H Smith Timothy Hla |
| author_facet | Colin Niaudet Bongnam Jung Andrew Kuo Steven Swendeman Edward Bull Takahiro Seno Reed Crocker Zhongjie Fu Lois E H Smith Timothy Hla |
| author_sort | Colin Niaudet |
| collection | DOAJ |
| description | Abstract Sphingosine‐1‐phosphate (S1P), the circulating HDL‐bound lipid mediator that acts via S1P receptors (S1PR), is required for normal vascular development. The role of this signaling axis in vascular retinopathies is unclear. Here, we show in a mouse model of oxygen‐induced retinopathy (OIR) that endothelial overexpression of S1pr1 suppresses while endothelial knockout of S1pr1 worsens neovascular tuft formation. Furthermore, neovascular tufts are increased in Apom−/− mice which lack HDL‐bound S1P while they are suppressed in ApomTG mice which have more circulating HDL‐S1P. These results suggest that circulating HDL‐S1P activation of endothelial S1PR1 suppresses neovascular pathology in OIR. Additionally, systemic administration of ApoM‐Fc‐bound S1P or a small‐molecule Gi‐biased S1PR1 agonist suppressed neovascular tuft formation. Circulating HDL‐S1P activation of endothelial S1PR1 may be a key protective mechanism to guard against neovascular retinopathies that occur not only in premature infants but also in diabetic patients and aging people. |
| format | Article |
| id | doaj-art-baf615af7db14d7584f85d219c23d926 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2023-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-baf615af7db14d7584f85d219c23d9262025-08-20T04:03:01ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-03-011551910.15252/emmm.202216645Therapeutic activation of endothelial sphingosine‐1‐phosphate receptor 1 by chaperone‐bound S1P suppresses proliferative retinal neovascularizationColin Niaudet0Bongnam Jung1Andrew Kuo2Steven Swendeman3Edward Bull4Takahiro Seno5Reed Crocker6Zhongjie Fu7Lois E H Smith8Timothy Hla9Department of Surgery, Vascular Biology Program, Boston Children's Hospital, Harvard Medical SchoolDepartment of Surgery, Vascular Biology Program, Boston Children's Hospital, Harvard Medical SchoolDepartment of Surgery, Vascular Biology Program, Boston Children's Hospital, Harvard Medical SchoolDepartment of Surgery, Vascular Biology Program, Boston Children's Hospital, Harvard Medical SchoolDepartment of Ophthalmology, Boston Children's Hospital, Harvard Medical SchoolDepartment of Surgery, Vascular Biology Program, Boston Children's Hospital, Harvard Medical SchoolDepartment of Surgery, Vascular Biology Program, Boston Children's Hospital, Harvard Medical SchoolDepartment of Ophthalmology, Boston Children's Hospital, Harvard Medical SchoolDepartment of Ophthalmology, Boston Children's Hospital, Harvard Medical SchoolDepartment of Surgery, Vascular Biology Program, Boston Children's Hospital, Harvard Medical SchoolAbstract Sphingosine‐1‐phosphate (S1P), the circulating HDL‐bound lipid mediator that acts via S1P receptors (S1PR), is required for normal vascular development. The role of this signaling axis in vascular retinopathies is unclear. Here, we show in a mouse model of oxygen‐induced retinopathy (OIR) that endothelial overexpression of S1pr1 suppresses while endothelial knockout of S1pr1 worsens neovascular tuft formation. Furthermore, neovascular tufts are increased in Apom−/− mice which lack HDL‐bound S1P while they are suppressed in ApomTG mice which have more circulating HDL‐S1P. These results suggest that circulating HDL‐S1P activation of endothelial S1PR1 suppresses neovascular pathology in OIR. Additionally, systemic administration of ApoM‐Fc‐bound S1P or a small‐molecule Gi‐biased S1PR1 agonist suppressed neovascular tuft formation. Circulating HDL‐S1P activation of endothelial S1PR1 may be a key protective mechanism to guard against neovascular retinopathies that occur not only in premature infants but also in diabetic patients and aging people.https://doi.org/10.15252/emmm.202216645neovascularizationSphingosine‐1‐phosphate (S1P)vascular retinopathy |
| spellingShingle | Colin Niaudet Bongnam Jung Andrew Kuo Steven Swendeman Edward Bull Takahiro Seno Reed Crocker Zhongjie Fu Lois E H Smith Timothy Hla Therapeutic activation of endothelial sphingosine‐1‐phosphate receptor 1 by chaperone‐bound S1P suppresses proliferative retinal neovascularization EMBO Molecular Medicine neovascularization Sphingosine‐1‐phosphate (S1P) vascular retinopathy |
| title | Therapeutic activation of endothelial sphingosine‐1‐phosphate receptor 1 by chaperone‐bound S1P suppresses proliferative retinal neovascularization |
| title_full | Therapeutic activation of endothelial sphingosine‐1‐phosphate receptor 1 by chaperone‐bound S1P suppresses proliferative retinal neovascularization |
| title_fullStr | Therapeutic activation of endothelial sphingosine‐1‐phosphate receptor 1 by chaperone‐bound S1P suppresses proliferative retinal neovascularization |
| title_full_unstemmed | Therapeutic activation of endothelial sphingosine‐1‐phosphate receptor 1 by chaperone‐bound S1P suppresses proliferative retinal neovascularization |
| title_short | Therapeutic activation of endothelial sphingosine‐1‐phosphate receptor 1 by chaperone‐bound S1P suppresses proliferative retinal neovascularization |
| title_sort | therapeutic activation of endothelial sphingosine 1 phosphate receptor 1 by chaperone bound s1p suppresses proliferative retinal neovascularization |
| topic | neovascularization Sphingosine‐1‐phosphate (S1P) vascular retinopathy |
| url | https://doi.org/10.15252/emmm.202216645 |
| work_keys_str_mv | AT colinniaudet therapeuticactivationofendothelialsphingosine1phosphatereceptor1bychaperonebounds1psuppressesproliferativeretinalneovascularization AT bongnamjung therapeuticactivationofendothelialsphingosine1phosphatereceptor1bychaperonebounds1psuppressesproliferativeretinalneovascularization AT andrewkuo therapeuticactivationofendothelialsphingosine1phosphatereceptor1bychaperonebounds1psuppressesproliferativeretinalneovascularization AT stevenswendeman therapeuticactivationofendothelialsphingosine1phosphatereceptor1bychaperonebounds1psuppressesproliferativeretinalneovascularization AT edwardbull therapeuticactivationofendothelialsphingosine1phosphatereceptor1bychaperonebounds1psuppressesproliferativeretinalneovascularization AT takahiroseno therapeuticactivationofendothelialsphingosine1phosphatereceptor1bychaperonebounds1psuppressesproliferativeretinalneovascularization AT reedcrocker therapeuticactivationofendothelialsphingosine1phosphatereceptor1bychaperonebounds1psuppressesproliferativeretinalneovascularization AT zhongjiefu therapeuticactivationofendothelialsphingosine1phosphatereceptor1bychaperonebounds1psuppressesproliferativeretinalneovascularization AT loisehsmith therapeuticactivationofendothelialsphingosine1phosphatereceptor1bychaperonebounds1psuppressesproliferativeretinalneovascularization AT timothyhla therapeuticactivationofendothelialsphingosine1phosphatereceptor1bychaperonebounds1psuppressesproliferativeretinalneovascularization |