Language
English
Publication Date
7-1-2024
Journal
Nature Cardiovascular Research
DOI
10.1038/s44161-024-00496-y
PMID
39196179
PMCID
PMC12306366
PubMedCentral® Posted Date
7-29-2025
PubMedCentral® Full Text Version
Author MSS
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.
Keywords
Animals, Smad5 Protein, Smad1 Protein, Kruppel-Like Transcription Factors, Vascular Remodeling, Humans, Stress, Mechanical, Disease Models, Animal, Mice, Mice, Inbred C57BL, Male, Endothelial Cells, Human Umbilical Vein Endothelial Cells, Mice, Knockout, Proto-Oncogene Proteins c-akt, Mechanotransduction, Cellular, Cells, Cultured, Signal Transduction
Published Open-Access
yes
Recommended Citation
Deng, Hanqiang; Zhang, Jiasheng; Wang, Yewei; et al., "A KLF2-Bmper-Smad1/5 Checkpoint Regulates High Fluid Shear Stress-Mediated Artery Remodeling" (2024). Faculty and Staff Publications. 4240.
https://digitalcommons.library.tmc.edu/baylor_docs/4240