ArticleThe Journal of clinical investigation2017
Laminar flow downregulates Notch activity to promote lymphatic sprouting.
Article in The Journal of clinical investigation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 93 papers.
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Who cites it
93 citing papers in PubMed, 137 citations in OpenAlex.
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- S1PR1 regulates lymphatic valve development and tertiary lymphoid organ formation in the ileum.The Journal of experimental medicine · 2025Article
- Meningeal lymphatic drainage: novel insights into central nervous system disease.Signal transduction and targeted therapy · 2025Review
- Understanding the Lymphatic System: Tissue-on-Chip Modeling.Annual review of biomedical engineering · 2025Review
- Multifaceted Role of Notch Signaling in Vascular Health and Diseases.Biomedicines · 2025Review
- Review
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- Regulation of VEGFR3 signaling in lymphatic endothelial cells.Frontiers in cell and developmental biology · 2025Review
- Three-Dimensional Lymphatics-on-a-Chip Reveals Distinct, Size-Dependent Nanoparticle Transport Mechanisms in Lymphatic Drug Delivery.ACS biomaterials science & engineering · 2024Article
- Meningeal Lymphatics in Central Nervous System Diseases.Annual review of neuroscience · 2024Review
- Human Cell-Derived Matrix Composite Hydrogels with Diverse Composition for Use in Vasculature-on-chip Models.Advanced healthcare materials · 2024Article
- Piezo1 regulates meningeal lymphatic vessel drainage and alleviates excessive CSF accumulation.Nature neuroscience · 2024Article
- Engineering Lymphangiogenesis-On-Chip: The Independent and Cooperative Regulation by Biochemical Factors, Gradients, and Interstitial Fluid Flow.Advanced biology · 2024Article
- Engineering models of head and neck and oral cancers on-a-chip.Biomicrofluidics · 2024Review
- Vascular organs-on-chip made with patient-derived endothelial cells: technologies to transform drug discovery and disease modeling.Expert opinion on drug discovery · 2024Review
33 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
19 authors at 6 institutions in 3 countries.
Funding
Abstract
The major function of the lymphatic system is to drain interstitial fluid from tissue. Functional drainage causes increased fluid flow that triggers lymphatic expansion, which is conceptually similar to hypoxia-triggered angiogenesis. Here, we have identified a mechanotransduction pathway that translates laminar flow-induced shear stress to activation of lymphatic sprouting. While low-rate laminar flow commonly induces the classic shear stress responses in blood endothelial cells and lymphatic endothelial cells (LECs), only LECs display reduced Notch activity and increased sprouting capacity. In response to flow, the plasma membrane calcium channel ORAI1 mediates calcium influx in LECs and activates calmodulin to facilitate a physical interaction between Krüppel-like factor 2 (KLF2), the major regulator of shear responses, and PROX1, the master regulator of lymphatic development. The PROX1/KLF2 complex upregulates the expression of DTX1 and DTX3L. DTX1 and DTX3L, functioning as a heterodimeric Notch E3 ligase, concertedly downregulate NOTCH1 activity and enhance lymphatic sprouting. Notably, overexpression of the calcium reporter GCaMP3 unexpectedly inhibited lymphatic sprouting, presumably by disturbing calcium signaling. Endothelial-specific knockouts of Orai1 and Klf2 also markedly impaired lymphatic sprouting. Moreover, Dtx3l loss of function led to defective lymphatic sprouting, while Dtx3l gain of function rescued impaired sprouting in Orai1 KO embryos. Together, the data reveal a molecular mechanism underlying laminar flow-induced lymphatic sprouting.
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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.