ArticleProceedings of the National Academy of Sciences of the United States of America2021
Activation of Smad2/3 signaling by low fluid shear stress mediates artery inward remodeling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 69 citations in OpenAlex.
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- Genetic and molecular mechanisms of hereditary thoracic aortic aneurysm and dissection (Review).Molecular medicine reports · 2026Review
- From Byproduct to Regulator: The Expanding Role of Lactate and Lactylation in Cardiovascular Physiology and Disease.Biology · 2026Review
- FOXO1 Integrates Endothelial Hemodynamic, Inflammatory, and Metabolic Pathways in Atherosclerosis.Circulation research · 2026Article
- Separating the genetics of disease, treatment, and treatment response using graphical modeling and large-scale electronic health records.medRxiv : the preprint server for health sciences · 2026Article
- Mechanoreceptor-mediated adaptations to physical exercise: from acute responses to long-term training effects.Cellular and molecular life sciences : CMLS · 2026Review
- Endothelial to mesenchymal transition in cardiovascular diseases: molecular insights and clinical perspectives.European heart journal · 2026Review
- Sildenafil suppresses the activation of hypertrophic scar fibroblasts by promoting the KLF15-mediated inhibition ofThe Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology · 2026Article
- Adaptation of plateau frog peptide: From antimicrobial to angiogenic and proliferative functions.Journal of advanced research · 2026Article
- Vascular remodeling enhances high-flow muscle oxygen delivery following aerobic exercise training.Frontiers in physiology · 2026Article
- Exercise-altered fluid shear stress regulates vascular endothelial inflammation via Piezo1.Frontiers in physiology · 2026Review
- TGF-β: The Molecular Mechanisms of Atherosclerosis - insights into SMAD Pathways and Gene Therapy Prospects.Current medicinal chemistry · 2026Review
- CILP attenuates pulmonary fibrosis through the TGF-β1/SMAD3 pathway.European journal of medical research · 2025Article
- Multidimensional optimization of stent design for endothelial shear stress regulation: Geometric structuring, surface functionalization strategies to mitigate thrombosis and restenosis.International journal of cardiology. Heart & vasculature · 2025Review
- [Role of the TGFZhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2025Review
- Hemodynamic forces prevent myxomatous valve disease in mice through KLF2/4 signaling.The Journal of clinical investigation · 2025Article
- Fluid Shear Stress-Regulated Vascular Remodeling: Past, Present, and Future.Arteriosclerosis, thrombosis, and vascular biology · 2025Review
- Vascular-type heterogeneity is associated with differential gene expression profiles of endothelial cells under shear stress.Research and practice in thrombosis and haemostasis · 2025Article
- Endothelial heterogeneity shapes shear stress response: a transcriptomic perspective.Research and practice in thrombosis and haemostasis · 2025Article
Corrections and comments
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Authors and funding
17 authors at 4 institutions in 3 countries.
Funding
Abstract
Endothelial cell (EC) sensing of wall fluid shear stress (FSS) from blood flow governs vessel remodeling to maintain FSS at a specific magnitude or set point in healthy vessels. Low FSS triggers inward remodeling to restore normal FSS but the regulatory mechanisms are unknown. In this paper, we describe the signaling network that governs inward artery remodeling. FSS induces Smad2/3 phosphorylation through the type I transforming growth factor (TGF)-β family receptor Alk5 and the transmembrane protein Neuropilin-1, which together increase sensitivity to circulating bone morphogenetic protein (BMP)-9. Smad2/3 nuclear translocation and target gene expression but not phosphorylation are maximal at low FSS and suppressed at physiological high shear. Reducing flow by carotid ligation in rodents increases Smad2/3 nuclear localization, while the resultant inward remodeling is blocked by the EC-specific deletion of Alk5. The flow-activated MEKK3/Klf2 pathway mediates the suppression of Smad2/3 nuclear translocation at high FSS, mainly through the cyclin-dependent kinase (CDK)-2-dependent phosphosphorylation of the Smad linker region. Thus, low FSS activates Smad2/3, while higher FSS blocks nuclear translocation to induce inward artery remodeling, specifically at low FSS. These results are likely relevant to inward remodeling in atherosclerotic vessels, in which Smad2/3 is activated through TGF-β signaling.
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