Pharmacological inhibition of FOXO1 promotes lymphatic valve growth in a congenital lymphedema mouse model
Mutations in many genes that regulate lymphatic valve development are associated with congenital lymphedema. Oscillatory shear stress (OSS) from lymph provides constant signals for the growth and maintenance of valve cells throughout life. The expression of valve-forming genes in lymphatic endotheli...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2022.1024628/full |
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| author | Ololade Ogunsina Richa Banerjee Luz A. Knauer Ying Yang |
| author_facet | Ololade Ogunsina Richa Banerjee Luz A. Knauer Ying Yang |
| author_sort | Ololade Ogunsina |
| collection | DOAJ |
| description | Mutations in many genes that regulate lymphatic valve development are associated with congenital lymphedema. Oscillatory shear stress (OSS) from lymph provides constant signals for the growth and maintenance of valve cells throughout life. The expression of valve-forming genes in lymphatic endothelial cells (LECs) is upregulated by OSS. The transcription factor FOXO1 represses lymphatic valve formation by inhibiting the expression of these genes, which makes FOXO1 a potential target for treating lymphedema. Here, we tested the ability of a FOXO1 inhibitor, AS1842856, to induce the formation of new lymphatic valves. Our quantitative RT-PCR and Western blot data showed that treatment of cultured human LECs with AS1842856 for 48 h significantly increased the expression levels of valve-forming genes. To investigate the function of AS1842856 in vivo, Foxc2+/− mice, the mouse model for lymphedema-distichiasis, were injected with AS1842856 for 2 weeks. The valve number in AS-treated Foxc2+/− mice was significantly higher than that of the vehicle-treated Foxc2+/− mice. Furthermore, since β-catenin upregulates the expression of Foxc2 and Prox1 during lymphatic valve formation, and AS1842856 treatment increased the level of active β-catenin in both cultured human LECs and in mouse mesenteric LECs in vivo, we used the mouse model with constitutive active β-catenin to rescue loss of lymphatic valves in Foxc2+/− mice. Foxc2+/− mice have 50% fewer lymphatic valves than control, and rescue experiments showed that the valve number was completely restored to the control level upon nuclear β-catenin activation. These findings indicate that pharmacological inhibition of FOXO1 can be explored as a viable strategy to resolve valve defects in congenital lymphedema. |
| first_indexed | 2024-04-10T21:52:40Z |
| format | Article |
| id | doaj.art-d06811de0cc9451d984940db5d12c3b1 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-04-10T21:52:40Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-d06811de0cc9451d984940db5d12c3b12023-01-18T11:52:42ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2023-01-011010.3389/fcell.2022.10246281024628Pharmacological inhibition of FOXO1 promotes lymphatic valve growth in a congenital lymphedema mouse modelOlolade OgunsinaRicha BanerjeeLuz A. KnauerYing YangMutations in many genes that regulate lymphatic valve development are associated with congenital lymphedema. Oscillatory shear stress (OSS) from lymph provides constant signals for the growth and maintenance of valve cells throughout life. The expression of valve-forming genes in lymphatic endothelial cells (LECs) is upregulated by OSS. The transcription factor FOXO1 represses lymphatic valve formation by inhibiting the expression of these genes, which makes FOXO1 a potential target for treating lymphedema. Here, we tested the ability of a FOXO1 inhibitor, AS1842856, to induce the formation of new lymphatic valves. Our quantitative RT-PCR and Western blot data showed that treatment of cultured human LECs with AS1842856 for 48 h significantly increased the expression levels of valve-forming genes. To investigate the function of AS1842856 in vivo, Foxc2+/− mice, the mouse model for lymphedema-distichiasis, were injected with AS1842856 for 2 weeks. The valve number in AS-treated Foxc2+/− mice was significantly higher than that of the vehicle-treated Foxc2+/− mice. Furthermore, since β-catenin upregulates the expression of Foxc2 and Prox1 during lymphatic valve formation, and AS1842856 treatment increased the level of active β-catenin in both cultured human LECs and in mouse mesenteric LECs in vivo, we used the mouse model with constitutive active β-catenin to rescue loss of lymphatic valves in Foxc2+/− mice. Foxc2+/− mice have 50% fewer lymphatic valves than control, and rescue experiments showed that the valve number was completely restored to the control level upon nuclear β-catenin activation. These findings indicate that pharmacological inhibition of FOXO1 can be explored as a viable strategy to resolve valve defects in congenital lymphedema.https://www.frontiersin.org/articles/10.3389/fcell.2022.1024628/fulllymphatic valvelymphedemaFOXO transcription factorsbeta-cateninvascular biologyAS1842856 |
| spellingShingle | Ololade Ogunsina Richa Banerjee Luz A. Knauer Ying Yang Pharmacological inhibition of FOXO1 promotes lymphatic valve growth in a congenital lymphedema mouse model Frontiers in Cell and Developmental Biology lymphatic valve lymphedema FOXO transcription factors beta-catenin vascular biology AS1842856 |
| title | Pharmacological inhibition of FOXO1 promotes lymphatic valve growth in a congenital lymphedema mouse model |
| title_full | Pharmacological inhibition of FOXO1 promotes lymphatic valve growth in a congenital lymphedema mouse model |
| title_fullStr | Pharmacological inhibition of FOXO1 promotes lymphatic valve growth in a congenital lymphedema mouse model |
| title_full_unstemmed | Pharmacological inhibition of FOXO1 promotes lymphatic valve growth in a congenital lymphedema mouse model |
| title_short | Pharmacological inhibition of FOXO1 promotes lymphatic valve growth in a congenital lymphedema mouse model |
| title_sort | pharmacological inhibition of foxo1 promotes lymphatic valve growth in a congenital lymphedema mouse model |
| topic | lymphatic valve lymphedema FOXO transcription factors beta-catenin vascular biology AS1842856 |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2022.1024628/full |
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