ArticlePLoS computational biology2009
Tipping the balance: robustness of tip cell selection, migration and fusion in angiogenesis.
Article in PLoS computational biology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 94 papers.
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Who cites it
94 citing papers in PubMed, 203 citations in OpenAlex.
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- Targeting stiffness-dependent YAP/TAZ restores angiogenesis dynamics impaired by ALK1 knockout in silico.PLoS computational biology · 2026Article
- COMMD9-regulated endothelial cell abnormality-induced hypercoagulability is associated with Budd-Chiari syndrome.International journal of surgery (London, England) · 2026Article
- Bmp9 regulates Notch signaling and the temporal dynamics of angiogenesis via Lunatic Fringe.Developmental cell · 2026Article
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- Temporal dynamics of angiogenesis: the emerging role of mechanoregulated pathways.Biochemical Society transactions · 2025Review
- Two critical events in the development of the vascular system: pruning and remodeling.Clinical and experimental medicine · 2025Review
- Interfacial energy constraints are sufficient to align cells over large distances.Biophysical journal · 2025Article
- A model of Notch signalling control of angiogenesis: Evidence of a role for Notch ligand heterodimerization.PLoS computational biology · 2025Article
- Identification of New Markers of Angiogenic Sprouting Using Transcriptomics: New Role for RND3.Arteriosclerosis, thrombosis, and vascular biology · 2024Article
- Bridging Scales: a Hybrid Model to Simulate Vascular Tumor Growth and Treatment Response.ArXiv · 2023Article
- Integrating a dynamic central metabolism model of cancer cells with a hybrid 3D multiscale model for vascular hepatocellular carcinoma growth.Scientific reports · 2022Article
- Engineered patterns of Notch ligands Jag1 and Dll4 elicit differential spatial control of endothelial sprouting.iScience · 2022Article
- VEGFR1 signaling in retinal angiogenesis and microinflammation.Progress in retinal and eye research · 2021Review
- Cerebrovascular development: mechanisms and experimental approaches.Cellular and molecular life sciences : CMLS · 2021Review
- Active perception during angiogenesis: filopodia speed up Notch selection of tip cellsPhilosophical transactions of the Royal Society of London. Series B, Biological sciences · 2021Article
- Pericyte migration and proliferation are tightly synchronized to endothelial cell sprouting dynamics.Integrative biology : quantitative biosciences from nano to macro · 2021Article
- The Activation of Endothelial Cells Relies on a Ferroptosis-Like Mechanism: Novel Perspectives in Management of Angiogenesis and Cancer Therapy.Frontiers in oncology · 2021Article
- Epigenetic Regulation of the Vascular Endothelium by Angiogenic LncRNAs.Frontiers in genetics · 2021Review
- A multiscale model of complex endothelial cell dynamics in early angiogenesis.PLoS computational biology · 2021Article
34 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Vascular abnormalities contribute to many diseases such as cancer and diabetic retinopathy. In angiogenesis new blood vessels, headed by a migrating tip cell, sprout from pre-existing vessels in response to signals, e.g., vascular endothelial growth factor (VEGF). Tip cells meet and fuse (anastomosis) to form blood-flow supporting loops. Tip cell selection is achieved by Dll4-Notch mediated lateral inhibition resulting, under normal conditions, in an interleaved arrangement of tip and non-migrating stalk cells. Previously, we showed that the increased VEGF levels found in many diseases can cause the delayed negative feedback of lateral inhibition to produce abnormal oscillations of tip/stalk cell fates. Here we describe the development and implementation of a novel physics-based hierarchical agent model, tightly coupled to in vivo data, to explore the system dynamics as perpetual lateral inhibition combines with tip cell migration and fusion. We explore the tipping point between normal and abnormal sprouting as VEGF increases. A novel filopodia-adhesion driven migration mechanism is presented and validated against in vivo data. Due to the unique feature of ongoing lateral inhibition, 'stabilised' tip/stalk cell patterns show sensitivity to the formation of new cell-cell junctions during fusion: we predict cell fates can reverse. The fusing tip cells become inhibited and neighbouring stalk cells flip fate, recursively providing new tip cells. Junction size emerges as a key factor in establishing a stable tip/stalk pattern. Cell-cell junctions elongate as tip cells migrate, which is shown to provide positive feedback to lateral inhibition, causing it to be more susceptible to pathological oscillations. Importantly, down-regulation of the migratory pathway alone is shown to be sufficient to rescue the sprouting system from oscillation and restore stability. Thus we suggest the use of migration inhibitors as therapeutic agents for vascular normalisation in cancer.
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Registered trials
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.