A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling.

Autor: Deng H; Yale Cardiovascular Research Center, Yale School of Medicine, New Haven, CT, USA.; Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA., Zhang J; Yale Cardiovascular Research Center, Yale School of Medicine, New Haven, CT, USA.; Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA., Wang Y; Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA., Joshi D; Yale Cardiovascular Research Center, Yale School of Medicine, New Haven, CT, USA., Pi X; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA., De Val S; Department of Physiology, Anatomy and Genetics, Institute of Developmental and Regenerative Medicine, University of Oxford, Oxford, UK., Schwartz MA; Yale Cardiovascular Research Center, Yale School of Medicine, New Haven, CT, USA. martin.schwartz@yale.edu.; Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. martin.schwartz@yale.edu.; Department of Cell Biology, Yale School of Medicine, and Department of Biomedical Engineering, Yale School of Engineering, New Haven, CT, USA. martin.schwartz@yale.edu.
Jazyk: angličtina
Zdroj: Nature cardiovascular research [Nat Cardiovasc Res] 2024 Jul; Vol. 3 (7), pp. 785-798. Date of Electronic Publication: 2024 Jul 08.
DOI: 10.1038/s44161-024-00496-y
Abstrakt: 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.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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