GO:1903671 negative regulation of sprouting angiogenesis: Signaling Axis, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1903671 describes any process that stops, prevents, or reduces the frequency, rate, or extent of sprouting angiogenesis, the formation of new blood vessels from existing ones.
• Key negative regulators include GPR182, which modulates CXCL12-CXCR4 signaling, and Nogo-A, which inhibits CNS angiogenesis.
• The KLF15/VASN axis activates Notch1 signaling to suppress angiogenesis, highlighting transcriptional and signaling crosstalk.
• Med23 supports angiogenesis by negatively regulating angiopoietin2 expression, illustrating context-dependent regulation.
• Dysregulation of sprouting angiogenesis is implicated in cancer, retinopathies, and cardiovascular diseases.
• CRISPR-based models (knockout, knock-in, overexpression) are essential to dissect these regulatory mechanisms.
Description
Sprouting angiogenesis is the process by which new blood vessels emerge from pre-existing vasculature, a critical event in development, wound healing, and tumor progression. The Gene Ontology term GO:1903671, negative regulation of sprouting angiogenesis, encompasses any process that stops, prevents, or reduces the frequency, rate, or extent of this sprouting. This regulatory mechanism is vital for maintaining vascular homeostasis and preventing pathological angiogenesis. Understanding the negative regulators of sprouting angiogenesis is essential for developing therapies against diseases characterized by excessive or insufficient vessel growth. Recent studies have identified diverse molecular players, including G protein-coupled receptors, transcription factors, and extracellular matrix components, that fine-tune this process. This article synthesizes current knowledge on GO:1903671, focusing on its definition, mechanisms, key genes, and research methodologies.
negative regulation of sprouting angiogenesis At A Glance
| GO ID | GO:1903671 |
|---|---|
| GO term | negative regulation of sprouting angiogenesis |
| Ontology | biological_process |
| Synonym | inhibition of sprouting angiogenesis |
| Major function | Inhibition of new blood vessel sprouting from existing vasculature |
| Related processes | Negative regulation of angiogenesis, regulation of sprouting angiogenesis |
| Key regulators | GPR182, Nogo-A, KLF15, VASN, Med23, DLC1, DOT1L |
| Disease relevance | Cancer, retinopathies, cardiovascular disorders, neurological diseases |
What Is GO:1903671?
GO:1903671, negative regulation of sprouting angiogenesis, is defined as any biological process that stops, prevents, or reduces the frequency, rate, or extent of sprouting angiogenesis. This includes molecular signals, cellular interactions, and environmental cues that inhibit the formation of new capillary sprouts from existing vessels. The term is a child of negative regulation of angiogenesis and regulation of sprouting angiogenesis, and it is distinct from positive regulation or the process itself.
Why Is negative regulation of sprouting angiogenesis Important in Cell Biology?
Negative regulation of sprouting angiogenesis is crucial for preventing excessive vascularization that can fuel tumor growth and for maintaining vascular quiescence in healthy tissues. Its dysregulation contributes to a wide range of pathologies, including cancer, where tumors hijack angiogenic signals, and ischemic diseases, where insufficient angiogenesis impairs tissue repair. Understanding these inhibitory mechanisms offers therapeutic opportunities to modulate angiogenesis in disease contexts.
• Prevents pathological angiogenesis in tumors and inflammatory diseases.
• Maintains vascular homeostasis and barrier integrity.
• Involved in CNS vascular development and blood-brain barrier function.
• Modulates response to anti-angiogenic therapies.
• Key for tissue repair and regeneration by limiting excessive sprouting.
• Implicated in diabetic retinopathy and age-related macular degeneration.
• Regulates immune cell trafficking through vascular normalization.
• Provides targets for CRISPR-based therapeutic intervention.
What Happens During negative regulation of sprouting angiogenesis?
Initiation of inhibitory signals
In simple terms: The process begins when molecules that stop blood vessel growth are produced or activated.
Negative regulation of sprouting angiogenesis is initiated by extracellular or intracellular signals that counteract pro-angiogenic cues. For example, the atypical chemokine receptor GPR182 negatively regulates sprouting angiogenesis by modulating CXCL12-CXCR4 axis signaling, thereby limiting endothelial cell migration and sprout formation. Similarly, Nogo-A acts as a negative regulator of CNS angiogenesis, inhibiting sprouting in the central nervous system.
Transcriptional and signaling cascades
In simple terms: These inhibitory signals turn on specific genes and pathways that block vessel sprouting.
Upon initiation, transcriptional programs are activated to sustain inhibition. The KLF15/VASN axis inhibits angiogenesis via activation of Notch1 signaling, leading to reduced endothelial sprouting. Additionally, DOT1L regulates MTDH-mediated angiogenesis in triple-negative breast cancer through the NF-κB-HIF1α axis, demonstrating epigenetic control of inhibitory pathways.
Cytoskeletal and adhesion remodeling
In simple terms: Cells change their shape and attachments to prevent them from moving and forming new branches.
Inhibition of sprouting requires dynamic changes in the cytoskeleton and focal adhesions. DLC1 promotes mechanotransductive feedback for YAP via RhoGAP-mediated focal adhesion turnover, which restricts endothelial cell migration and sprout formation. This remodeling ensures that endothelial cells remain quiescent and do not form new sprouts.
Extracellular matrix and microenvironment interactions
In simple terms: The environment around the cells also sends stop signals.
The extracellular matrix and neighboring cells contribute to negative regulation. Aged fibroblast-derived extracellular vesicles promote angiogenesis in melanoma, but under certain conditions, they can also carry inhibitory signals. Med23 supports angiogenesis and maintains vascular integrity through negative regulation of angiopoietin2 expression, highlighting the role of microenvironmental cues.
Integration and feedback
In simple terms: The stop signals are integrated to ensure balanced vessel growth.
Multiple inhibitory pathways converge to fine-tune angiogenesis. For instance, BCR::ABL1 tyrosine kinase inhibitors such as ponatinib and nilotinib differentially affect endothelial angiogenesis and signalling, demonstrating pharmacological modulation of these pathways. This integration prevents excessive sprouting and maintains vascular homeostasis.
Key Genes Involved in GO:1903671 negative regulation of sprouting angiogenesis
The following genes and proteins have been experimentally implicated in the negative regulation of sprouting angiogenesis, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| GPR182 | Negatively regulates sprouting angiogenesis via CXCL12-CXCR4 axis | Potential target for anti-angiogenic therapy |
| Nogo-A | Negative regulator of CNS angiogenesis | Implicated in neurological vascular disorders |
| KLF15 | Transcription factor inhibiting angiogenesis via Notch1 | Regulates endothelial quiescence |
| VASN | Activates Notch1 signaling to inhibit angiogenesis | Modulates vascular development |
| Med23 | Supports angiogenesis by negatively regulating angiopoietin2 | Maintains vascular integrity |
| DLC1 | Promotes focal adhesion turnover via RhoGAP | Regulates mechanotransduction |
| DOT1L | Epigenetic regulator of MTDH-mediated angiogenesis | Involved in triple-negative breast cancer |
| MTDH | Mediates angiogenesis via NF-κB-HIF1α axis | Therapeutic target in breast cancer |
| YAP | Effector of mechanotransductive feedback | Regulates endothelial cell behavior |
| Angiopoietin2 | Pro-angiogenic factor negatively regulated by Med23 | Vascular destabilization |
| CXCR4 | Receptor for CXCL12, modulated by GPR182 | Chemokine signaling in angiogenesis |
| CXCL12 | Chemokine ligand, modulated by GPR182 | Regulates endothelial migration |
| Notch1 | Signaling receptor activated by KLF15/VASN | Inhibits sprouting angiogenesis |
| HIF1α | Transcription factor regulated by DOT1L/MTDH | Hypoxia response in cancer |
| NF-κB | Transcription factor in DOT1L/MTDH axis | Inflammatory signaling |
| RhoA | Small GTPase regulated by DLC1 | Cytoskeletal dynamics |
How Is negative regulation of sprouting angiogenesis Regulated?
The negative regulation of sprouting angiogenesis is itself subject to regulation by various upstream signals. For example, the BCR::ABL1 tyrosine kinase inhibitors ponatinib and nilotinib differentially affect endothelial angiogenesis and signalling, indicating that tyrosine kinase activity can modulate inhibitory pathways. Additionally, the KLF15/VASN axis activates Notch1 signaling, which is a key inhibitory pathway. Med23 regulates angiopoietin2 expression, affecting vascular stability. These examples illustrate that negative regulation is tightly controlled by transcriptional, signaling, and pharmacological inputs.
negative regulation of sprouting angiogenesis and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| DOT1L | Triple-negative breast cancer | Knockout in MDA-MB-231 cells |
| Nogo-A | CNS angiogenesis disorders | Knockout in mouse brain endothelial cells |
| GPR182 | Angiogenesis-related pathologies | Knockout in zebrafish or HUVECs |
| Med23 | Vascular integrity defects | Endothelial-specific knockout mice |
| KLF15 | Vascular quiescence | Overexpression in HUVECs |
Cancer
In cancer, negative regulation of sprouting angiogenesis is often dysregulated to promote tumor vascularization. DOT1L regulates MTDH-mediated angiogenesis in triple-negative breast cancer through the NF-κB-HIF1α axis, and its inhibition can suppress tumor growth. Aged fibroblast-derived extracellular vesicles promote angiogenesis in melanoma, highlighting the role of the tumor microenvironment in overcoming negative regulation. Targeting these pathways with CRISPR-based approaches could restore inhibitory control.
Neurological disorders
Nogo-A is a negative regulator of CNS angiogenesis, and its dysfunction is implicated in neurological disorders characterized by aberrant vascularization. The blood-brain barrier integrity relies on proper negative regulation of sprouting angiogenesis, and its disruption contributes to conditions such as stroke and neurodegeneration.
Cardiovascular diseases
Dysregulation of sprouting angiogenesis contributes to cardiovascular diseases. Med23 supports angiogenesis and maintains vascular integrity through negative regulation of angiopoietin2 expression, and its loss leads to vascular leakage. GPR182 negatively regulates sprouting angiogenesis via modulating CXCL12-CXCR4 axis signaling, and its modulation could affect ischemic diseases.
From negative regulation of sprouting angiogenesis-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does GPR182 inhibit sprouting angiogenesis? | Knockout of GPR182 in endothelial cells |
| What is the role of KLF15/VASN in Notch1 activation? | Knock-in of VASN mutations |
| How does Med23 regulate angiopoietin2? | Endothelial-specific Med23 knockout |
| Does DLC1 affect focal adhesion turnover? | Point mutations in DLC1 RhoGAP domain |
| Can DOT1L inhibition suppress tumor angiogenesis? | Overexpression of DOT1L in breast cancer cells |
| What is the effect of Nogo-A on CNS angiogenesis? | Nogo-A knockout mice |
How to Study the negative regulation of sprouting angiogenesis Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout screening | Loss-of-function effects on angiogenesis | Identify negative regulators |
| RNA-seq | Transcriptional changes | Validate downstream pathways |
| Proteomics | Protein expression and interactions | Study signaling complexes |
| Phosphoproteomics | Phosphorylation events | Analyze kinase pathways |
| 3D sprouting assay | Endothelial sprout formation | Test gene function in vitro |
| Mouse retina angiogenesis | In vivo sprouting | Study developmental angiogenesis |
| Zebrafish angiogenesis | Vascular development | High-throughput genetic studies |
CRISPR screening
Genome-wide CRISPR knockout screens can identify novel negative regulators of sprouting angiogenesis. For example, a screen in endothelial cells under angiogenic conditions could reveal genes whose loss increases sprouting.
RNA sequencing
RNA-seq of endothelial cells with manipulated candidate genes can uncover transcriptional changes in angiogenic pathways. This is useful to validate the impact of genes like KLF15 or Med23 on downstream targets.
Proteomics and phosphoproteomics
Mass spectrometry-based proteomics can identify protein interactions and signaling changes. For instance, studying DLC1-mediated focal adhesion turnover requires phosphoproteomic analysis.
Imaging-based assays
Live-cell imaging of endothelial sprouting in 3D matrices or in vivo models (e.g., zebrafish, mouse retina) allows direct visualization of negative regulation. This is critical for studying GPR182 and Nogo-A.
How CRISPR Can Be Used to Study GO:1903671 negative regulation of sprouting angiogenesis
Knockout
CRISPR knockout of candidate negative regulators such as GPR182 or Nogo-A can lead to increased sprouting angiogenesis, confirming their inhibitory roles. This approach is fundamental for loss-of-function studies.
Point Mutation
Introducing point mutations in genes like DLC1 can dissect specific domains required for its RhoGAP activity and focal adhesion turnover, linking molecular function to angiogenic regulation.
Knock-in
Knock-in of tagged versions of proteins (e.g., KLF15, VASN) allows for localization and interaction studies, revealing how they activate Notch1 signaling to inhibit angiogenesis.
Overexpression
Overexpression of negative regulators such as KLF15 or VASN can suppress angiogenesis, providing gain-of-function evidence and potential therapeutic strategies.
How EDITGENE Supports negative regulation of sprouting angiogenesis Research
Researchers studying negative regulation of sprouting angiogenesis-related genes often need to determine whether a candidate gene is causally involved in the process or merely correlated. EDITGENE provides a comprehensive suite of CRISPR services to enable such causal studies, from knockout to precise point mutations and overexpression, ensuring publication-ready results.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of sprouting angiogenesis research.
Frequently Asked Questions About negative regulation of sprouting angiogenesis
What is GO:1903671?
GO:1903671 is the Gene Ontology term for negative regulation of sprouting angiogenesis, defined as any process that stops, prevents, or reduces the frequency, rate, or extent of sprouting angiogenesis.
What genes are involved in negative regulation of sprouting angiogenesis?
Key genes include GPR182, Nogo-A, KLF15, VASN, Med23, DLC1, and DOT1L, among others.
How does GPR182 inhibit angiogenesis?
GPR182 negatively regulates sprouting angiogenesis by modulating CXCL12-CXCR4 axis signaling, reducing endothelial cell migration and sprout formation.
What is the role of Nogo-A in CNS angiogenesis?
Nogo-A acts as a negative regulator of CNS angiogenesis, inhibiting sprouting in the central nervous system.
How does KLF15/VASN axis suppress angiogenesis?
The KLF15/VASN axis inhibits angiogenesis via activation of Notch1 signaling, leading to reduced endothelial sprouting.
What diseases are associated with dysregulated sprouting angiogenesis?
Dysregulation is implicated in cancer, neurological disorders, cardiovascular diseases, and retinopathies.
What research methods are used to study negative regulation of sprouting angiogenesis?
Common methods include CRISPR screening, RNA-seq, proteomics, and imaging-based assays.
How can CRISPR be used to study this process?
CRISPR knockout, point mutation, knock-in, and overexpression models allow causal interrogation of candidate genes.
What is the role of Med23 in angiogenesis?
Med23 supports angiogenesis and maintains vascular integrity through negative regulation of angiopoietin2 expression.
How does DLC1 regulate angiogenesis?
DLC1 promotes mechanotransductive feedback for YAP via RhoGAP-mediated focal adhesion turnover, restricting endothelial cell migration.
Conclusion
Negative regulation of sprouting angiogenesis (GO:1903671) is a critical biological process that maintains vascular homeostasis and prevents pathological vessel growth. Key regulators such as GPR182, Nogo-A, and the KLF15/VASN axis provide promising targets for therapeutic intervention in cancer, neurological, and cardiovascular diseases. Advances in CRISPR-based models and multi-omics approaches are accelerating the discovery of new players and mechanisms, paving the way for precision medicine.
References
- 1. Zibrova D et al.. 2025. The BCR::ABL1 tyrosine kinase inhibitors ponatinib and nilotinib differentially affect endothelial angiogenesis and signalling.. Mol Cell Biochem 480(3):1627-1643 PMID: 39009935
- 2. Zhang J et al.. 2025. Endothelial KLF15/VASN Axis Inhibits Angiogenesis via Activation of Notch1 Signaling.. Circ Res 136(12):1595-1609 PMID: 40297901
- 3. Yang Y et al.. 2022. Med23 supports angiogenesis and maintains vascular integrity through negative regulation of angiopoietin2 expression.. Commun Biol 5(1):374 PMID: 35440711
- 4. Hüser L et al.. 2024. Aged fibroblast-derived extracellular vesicles promote angiogenesis in melanoma.. Cell Rep 43(9):114721 PMID: 39255061
- 5. Hooglugt A et al.. 2024. DLC1 promotes mechanotransductive feedback for YAP via RhoGAP-mediated focal adhesion turnover.. J Cell Sci 137(8) PMID: 38563084
- 6. Neeli PK et al.. 2023. DOT1L regulates MTDH-mediated angiogenesis in triple-negative breast cancer: intermediacy of NF-κB-HIF1α axis.. FEBS J 290(2):502-520 PMID: 36017623
- 7. Wälchli T et al.. 2013. Nogo-A is a negative regulator of CNS angiogenesis.. Proc Natl Acad Sci U S A 110(21):E1943-52 PMID: 23625008
- 8. Chen C et al.. 2025. G protein-coupled receptor GPR182 negatively regulates sprouting angiogenesis via modulating CXCL12-CXCR4 axis signaling.. Angiogenesis 28(3):25 PMID: 40314798
