ArticleThe Journal of clinical investigation2023
SMAD4 maintains the fluid shear stress set point to protect against arterial-venous malformations.
Article in The Journal of clinical investigation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 43 citations in OpenAlex.
- c-KIT expands the tool kit for treating arteriovenous malformation.The Journal of clinical investigation · 2026Article
- G Protein-Coupled Receptor in High-Altitude Diseases: Mechanistic Insights and Therapeutic Opportunities.MedComm · 2026Review
- Loss of Smad4 drives vascular malformations via c-KIT-dependent high-fluid shear stress mimicry.The Journal of clinical investigation · 2026Article
- Extracellular matrix remodeling and internal elastic lamina alterations in cerebral arteriovenous malformations: Insights into vascular wall biology.Neurosurgical review · 2026Review
- Gene-Specific Endothelial Programs Drive AVM Pathogenesis inArteriosclerosis, thrombosis, and vascular biology · 2026Article
- Review
- Proteomic Profiling of Endothelial Cells Under Laminar Shear Stress Confirms the Importance of KLF4 in the Regulation of Membrane Protein Expression Compared to Oscillatory Flow.Journal of proteome research · 2026Article
- Coronary endothelial cells undergo venous-enriched disrupted maturation following myocardial infarction.Basic research in cardiology · 2026Article
- Article
- Multiomic Reference Map of Endothelial Mechanosensitive Pathways Under Athero- and Erosion-Prone Flow.Journal of the American Heart Association · 2026Article
- Regulation of endothelial cell chromatin availability and transcription factor activity during arterial-venous specification.Development (Cambridge, England) · 2026Article
- Nitazoxanide activates BMP9-ALK1-SMAD signaling cascade and improves HHT vascular pathology.bioRxiv : the preprint server for biology · 2026Article
- Mothers against decapentaplegic homolog 4 as a proteomic hub in vascular remodeling and residual cardiovascular risk.World journal of cardiology · 2026Article
- Article
- Flow-induced Klf4-Akt signaling links EC cycling to mural cell defects in arterial-venous malformations.Theranostics · 2026Article
- Feeding artery remodeling and long-term regression of flow related aneurysms following obliteration of brain arteriovenous malformations.Brain & spine · 2026Article
- PI3K/AKT/mTOR axis in vascular malformations: from molecular insights to targeted clinical trials.Orphanet journal of rare diseases · 2025Review
- Disrupted Vessels-Connected Voices: Why Patient Partnership and Cross-Disease Collaboration Are Essential for Accelerating HHT Research.Biomedicines · 2025Article
- Artery formation in the intestinal wall and mesentery by intestine-derived Esm1+ endothelial cells.Nature communications · 2025Article
- PIEZO1 Overexpression in Hereditary Hemorrhagic Telangiectasia Arteriovenous Malformations.Circulation · 2025Article
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 3 countries.
Funding
Abstract
Vascular networks form, remodel, and mature under the influence of both fluid shear stress (FSS) and soluble factors. Physiological FSS promotes and maintains vascular stability via synergy with bone morphogenic proteins 9 and 10 (BMP9 and BMP10). Conversely, mutation of the BMP receptors activin-like kinase 1 (ALK1), endoglin (ENG), or the downstream effector, SMAD family member 4 (SMAD4) leads to hereditary hemorrhagic telangiectasia (HHT), characterized by fragile and leaky arterial-venous malformations (AVMs). How endothelial cells (ECs) integrate FSS and BMP signals in vascular development and homeostasis and how mutations give rise to vascular malformations is not well understood. Here, we aimed to elucidate the mechanism of synergy between FSS and SMAD signaling in vascular stability and how disruption of this synergy leads to AVMs. We found that loss of Smad4 increased the sensitivity of ECs to flow by lowering the FSS set point, with resulting AVMs exhibiting features of excessive flow-mediated morphological responses. Mechanistically, loss of SMAD4 disinhibits flow-mediated KLF4-TIE2-PI3K/Akt signaling, leading to cell cycle progression-mediated loss of arterial identity due to KLF4-mediated repression of cyclin dependent Kinase (CDK) inhibitors CDKN2A and CDKN2B. Thus, AVMs caused by Smad4 deletion are characterized by chronic high flow remodeling with excessive EC proliferation and loss of arterial identity as triggering events.
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