ArticleArteriosclerosis, thrombosis, and vascular biology2015
DLL4/Notch1 and BMP9 Interdependent Signaling Induces Human Endothelial Cell Quiescence via P27KIP1 and Thrombospondin-1.
Article in Arteriosclerosis, thrombosis, and vascular biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 61 citations in OpenAlex.
- FKBP12 determines ligand-specific SMAD signaling in individual living endothelial cells.iScience · 2026Article
- The NOTCH3 extracellular domain is a serum biomarker for pulmonary arterial hypertension.Nature medicine · 2026Article
- Same same but different? How blood and lymphatic vessels induce cell contact inhibition.Biochemical Society transactions · 2025Review
- Multiscale computational model predicts how environmental changes and treatments affect microvascular remodeling in fibrotic disease.PNAS nexus · 2025Article
- Akt3 activation by R-Ras in an endothelial cell enforces quiescence and barrier stability of neighboring endothelial cells via Jagged1.Cell reports · 2024Article
- Multiscale computational model predicts how environmental changes and drug treatments affect microvascular remodeling in fibrotic disease.bioRxiv : the preprint server for biology · 2024Article
- Large-scale phosphoproteomics reveals activation of the MAPK/GADD45β/P38 axis and cell cycle inhibition in response to BMP9 and BMP10 stimulation in endothelial cells.Cell communication and signaling : CCS · 2024Article
- Thrombospondin-1 in vascular development, vascular function, and vascular disease.Seminars in cell & developmental biology · 2024Review
- Tensile Stress-Activated and Exosome-Transferred YAP/TAZ-Notch Circuit Specifies Type H Endothelial Cell for Segmental Bone Regeneration.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Hereditary hemorrhagic telangiectasia: from signaling insights to therapeutic advances.The Journal of clinical investigation · 2024Review
- Purification of functional mouse skeletal muscle mitochondria using percoll density gradient centrifugation.BMC research notes · 2023Article
- Fluid shear stress-modulated chromatin accessibility reveals the mechano-dependency of endothelial SMAD1/5-mediated gene transcription.iScience · 2023Article
- Endothelial tip/stalk cell selection requires BMP9-induced βMolecular biology of the cell · 2023Article
- Notch Signaling in the Vasculature: Angiogenesis and Angiocrine Functions.Cold Spring Harbor perspectives in medicine · 2023Review
- Pericytes and vascular smooth muscle cells in central nervous system arteriovenous malformations.Frontiers in physiology · 2023Review
- Metabolic Reprogramming in Tumor Endothelial Cells.International journal of molecular sciences · 2022Review
- Rethinking growth factors: the case of BMP9 during vessel maturation.Vascular biology (Bristol, England) · 2022Review
- Notch activation promotes endothelial quiescence by repressing MYC expression via miR-218.Molecular therapy. Nucleic acids · 2021Article
- Notch2 suppression mimicking changes in human pulmonary hypertension modulates Notch1 and promotes endothelial cell proliferation.American journal of physiology. Heart and circulatory physiology · 2021Article
- The quiescent endothelium: signalling pathways regulating organ-specific endothelial normalcy.Nature reviews. Cardiology · 2021Review
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
objectiveBone morphogenetic protein-9 (BMP9)/activin-like kinase-1 and delta-like 4 (DLL4)/Notch promote endothelial quiescence, and we aim to understand mechanistic interactions between the 2 pathways. We identify new targets that contribute to endothelial quiescence and test whether loss of Dll4(+/-) in adult vasculature alters BMP signaling. APPROACH AND
resultsHuman endothelial cells respond synergistically to BMP9 and DLL4 stimulation, showing complete quiescence and induction of HEY1 and HEY2. Canonical BMP9 signaling via activin-like kinase-1-Smad1/5/9 was disrupted by inhibition of Notch signaling, even in the absence of exogenous DLL4. Similarly, DLL4 activity was suppressed when the basal activin-like kinase-1-Smad1/5/9 pathway was inhibited, showing that these pathways are interdependent. BMP9/DLL4 required induction of P27(KIP1) for quiescence, although multiple factors are involved. To understand these mechanisms, we used proteomics data to identify upregulation of thrombospondin-1, which contributes to the quiescence phenotype. To test whether Dll4 regulates BMP/Smad pathways and endothelial cell phenotype in vivo, we characterized the vasculature of Dll4(+/-) mice, analyzing endothelial cells in the lung, heart, and aorta. Together with changes in endothelial structure and vascular morphogenesis, we found that loss of Dll4 was associated with a significant upregulation of pSmad1/5/9 signaling in lung endothelial cells. Because steady-state endothelial cell proliferation rates were not different in the Dll4(+/-) mice, we propose that the upregulation of pSmad1/5/9 signaling compensates to maintain endothelial cell quiescence in these mice.
conclusionsDLL4/Notch and BMP9/activin-like kinase-1 signaling rely on each other's pathways for full activity. This represents an important mechanism of cross talk that enhances endothelial quiescence and sensitively coordinates cellular responsiveness to soluble and cell-tethered ligands.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.