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A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling.
- Source :
-
Nature cardiovascular research [Nat Cardiovasc Res] 2024 Jul; Vol. 3 (7), pp. 785-798. Date of Electronic Publication: 2024 Jul 08. - Publication Year :
- 2024
-
Abstract
- 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.<br /> (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
- Subjects :
- Animals
Humans
Stress, Mechanical
Disease Models, Animal
Mice
Mice, Inbred C57BL
Male
Endothelial Cells metabolism
Human Umbilical Vein Endothelial Cells
Mice, Knockout
Proto-Oncogene Proteins c-akt metabolism
Mechanotransduction, Cellular
Cells, Cultured
Signal Transduction
Smad5 Protein metabolism
Smad5 Protein genetics
Smad1 Protein metabolism
Smad1 Protein genetics
Kruppel-Like Transcription Factors metabolism
Kruppel-Like Transcription Factors genetics
Vascular Remodeling physiology
Subjects
Details
- Language :
- English
- ISSN :
- 2731-0590
- Volume :
- 3
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Nature cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 39196179
- Full Text :
- https://doi.org/10.1038/s44161-024-00496-y