A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling
Vascular remodeling to match arterial diameter to tissue requirements commonly fails in ischemic disease. Endothelial cells sense fluid shear stress (FSS) from blood flow to maintain FSS within a narrow range in healthy vessels. Thus, high FSS induces vessel outward remodeling, but mechanisms are po...
| Päätekijät: | , , , , , , |
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| Aineistotyyppi: | Journal article |
| Kieli: | English |
| Julkaistu: |
Springer Nature
2024
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| _version_ | 1826316991677333504 |
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| author | Deng, H Zhang, J Wang, Y Joshi, D Pi, X De Val, S Schwartz, MA |
| author_facet | Deng, H Zhang, J Wang, Y Joshi, D Pi, X De Val, S Schwartz, MA |
| author_sort | Deng, H |
| collection | OXFORD |
| description | Vascular remodeling to match arterial diameter to tissue requirements commonly fails in ischemic disease. Endothelial cells sense fluid shear stress (FSS) from blood flow to maintain FSS within a narrow range in healthy vessels. Thus, high FSS induces vessel outward remodeling, but mechanisms are poorly understood. We previously reported that Smad1/5 is maximally activated at physiological FSS. Smad1/5 limits Akt activation, suggesting that inhibiting Smad1/5 may facilitate outward remodeling. Here we report that high FSS suppresses Smad1/5 by elevating KLF2, which induces the bone morphogenetic protein (BMP) pathway inhibitor, BMP-binding endothelial regulator (BMPER), thereby de-inhibiting Akt. In mice, surgically induced high FSS elevated BMPER expression, inactivated Smad1/5 and induced vessel outward remodeling. Endothelial BMPER deletion impaired blood flow recovery and vascular remodeling. Blocking endothelial cell Smad1/5 activation with BMP9/10 blocking antibodies improved vascular remodeling in mouse models of type 1 and type 2 diabetes. Suppression of Smad1/5 is thus a potential therapeutic approach for ischemic disease. |
| first_indexed | 2024-12-09T03:26:19Z |
| format | Journal article |
| id | oxford-uuid:655bddff-fec4-4e3c-b2b5-cb5d537cb10c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2025-02-19T04:31:31Z |
| publishDate | 2024 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:655bddff-fec4-4e3c-b2b5-cb5d537cb10c2025-01-08T07:40:05ZA KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodelingJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:655bddff-fec4-4e3c-b2b5-cb5d537cb10cEnglishSymplectic ElementsSpringer Nature2024Deng, HZhang, JWang, YJoshi, DPi, XDe Val, SSchwartz, MAVascular remodeling to match arterial diameter to tissue requirements commonly fails in ischemic disease. Endothelial cells sense fluid shear stress (FSS) from blood flow to maintain FSS within a narrow range in healthy vessels. Thus, high FSS induces vessel outward remodeling, but mechanisms are poorly understood. We previously reported that Smad1/5 is maximally activated at physiological FSS. Smad1/5 limits Akt activation, suggesting that inhibiting Smad1/5 may facilitate outward remodeling. Here we report that high FSS suppresses Smad1/5 by elevating KLF2, which induces the bone morphogenetic protein (BMP) pathway inhibitor, BMP-binding endothelial regulator (BMPER), thereby de-inhibiting Akt. In mice, surgically induced high FSS elevated BMPER expression, inactivated Smad1/5 and induced vessel outward remodeling. Endothelial BMPER deletion impaired blood flow recovery and vascular remodeling. Blocking endothelial cell Smad1/5 activation with BMP9/10 blocking antibodies improved vascular remodeling in mouse models of type 1 and type 2 diabetes. Suppression of Smad1/5 is thus a potential therapeutic approach for ischemic disease. |
| spellingShingle | Deng, H Zhang, J Wang, Y Joshi, D Pi, X De Val, S Schwartz, MA A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling |
| title | A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling |
| title_full | A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling |
| title_fullStr | A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling |
| title_full_unstemmed | A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling |
| title_short | A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling |
| title_sort | klf2 bmper smad1 5 checkpoint regulates high fluid shear stress mediated artery remodeling |
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