GO:1902548 negative regulation of cellular response to vascular endothelial growth factor stimulus: Signaling Brake, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1902548 describes any process that stops, prevents, or reduces the cellular response to VEGF, VEGF-A, or VEGF-B stimulation.
• This negative regulation is essential for balancing angiogenesis, vascular permeability, and endothelial survival.
• Key molecular brakes include Rho kinase, PI3K/Akt modulators, and HIF-1α-dependent feedback.
• Dysregulation of this term is linked to cancer, ischemic injury, and chronic inflammatory diseases.
• CRISPR knockout, point mutation, knock-in, and overexpression models enable causal dissection of these brakes.
• EDITGENE provides end-to-end CRISPR services to study this pathway in relevant cell models.
Description
The Gene Ontology term GO:1902548, negative regulation of cellular response to vascular endothelial growth factor stimulus, defines any process that stops, prevents, or reduces the frequency, rate, or extent of a cell's response to VEGF, VEGF-A, or VEGF-B. VEGF signaling is a central driver of angiogenesis, vascular permeability, and endothelial cell survival, and its negative regulation is critical for preventing excessive or aberrant vessel growth. Researchers study this term to understand how cells dampen VEGF-driven signals in development, tissue repair, and disease. The QuickGO definition encompasses both direct inhibition of VEGF receptors and downstream modulation of signaling cascades. This article synthesizes published evidence on the mechanisms, key genes, disease relevance, and CRISPR-based research methods for GO:1902548.
negative regulation of cellular response to vascular endothelial growth factor stimulus At A Glance
| GO ID | GO:1902548 |
|---|---|
| GO term | negative regulation of cellular response to vascular endothelial growth factor stimulus |
| Ontology | biological_process |
| Synonym | down regulation of cellular response to VEGF; inhibition of cellular response to VEGFA; negative regulation of cellular response to VEGFB |
| Major function | Dampening VEGF-driven angiogenesis, permeability, and survival signals |
| Definition source | QuickGO |
| Related ligands | VEGF, VEGF-A, VEGF-B |
| Cellular context | Endothelial cells, cancer cells, stromal cells |
What Is GO:1902548?
In simple terms, GO:1902548 is the cellular brake on VEGF signaling. It includes any molecular event that reduces how strongly a cell responds to VEGF stimulation, whether by blocking receptor activation, degrading signaling intermediates, or inducing negative feedback loops. This term is a biological process and applies to all cell types that respond to VEGF family ligands, especially endothelial cells.
Why Is negative regulation of cellular response to vascular endothelial growth factor stimulus Important in Cell Biology?
GO:1902548 is important because VEGF signaling is a master regulator of blood vessel formation and vascular homeostasis, and its negative regulation prevents pathological angiogenesis, edema, and tumor progression. Understanding this term helps researchers identify therapeutic targets for diseases where VEGF responses are too high or too low, such as cancer, retinopathies, and ischemic injury.
• Balances angiogenesis to avoid excessive vessel sprouting.
• Controls vascular permeability in inflammation and injury.
• Modulates endothelial cell survival and apoptosis.
• Influences tumor microenvironment and cancer progression.
• Affects response to hypoxia and metabolic stress.
• Plays a role in myocardial infarction and cardiac repair.
• Contributes to neuroprotective mechanisms after ischemia-reperfusion.
• Provides targets for anti-angiogenic therapies.
• Helps explain resistance to VEGF-blocking drugs.
• Guides CRISPR-based functional genomics screens.
What Happens During negative regulation of cellular response to vascular endothelial growth factor stimulus?
Receptor-level inhibition
In simple terms: The cell reduces the number or activity of VEGF receptors on its surface.
Negative regulation can occur by downregulating VEGFR2 expression, promoting receptor internalization, or blocking ligand binding. For example, Rho kinase activity downstream of G(ialpha2) modulates VEGF-induced endothelial cell chemotaxis, effectively dampening the response. This step prevents excessive receptor activation and downstream signaling.
Downstream signaling brakes
In simple terms: Inside the cell, specific enzymes put the brakes on VEGF-activated pathways.
The PI3K/Akt pathway is a major VEGF effector, and its negative regulation can occur through phosphatases or inhibitory proteins. RANKL regulates endothelial cell survival through PI3K/Akt, and interference with this axis can reduce VEGF-driven survival signals. Such brakes ensure that Akt activation is transient and spatially controlled.
Hypoxia and HIF-1α feedback
In simple terms: Low oxygen usually boosts VEGF, but feedback loops can later suppress the response.
HIF-1α is stabilized by hypoxia and drives VEGF transcription, but normoxic induction of HIF-1α by adenosine-A2B receptor signaling in epicardial stromal cells can modulate VEGF responses in the post-infarct heart. Skeletal muscle HIF-1 and exercise also influence VEGF-related adaptations, showing that oxygen-sensing pathways intersect with negative regulation.
Inflammatory and metabolic modulation
In simple terms: Diet and inflammation can change how strongly cells react to VEGF.
Anti-inflammatory diets may reduce VEGF-driven inflammatory signaling, indirectly contributing to negative regulation of cellular responses to VEGF. Insulin-like growth factor binding protein 5 (IGFBP5) is a probable target in kidney renal papillary renal cell carcinoma and may influence VEGF-related pathways. These examples highlight systemic modulation of GO:1902548.
Key Genes Involved in GO:1902548 negative regulation of cellular response to vascular endothelial growth factor stimulus
The following genes and proteins have been experimentally linked to negative regulation of cellular response to VEGF stimulus, based on the verified literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| RHOA | Mediates Rho kinase-dependent dampening of VEGF chemotaxis | Target for endothelial migration studies |
| PIK3CA | PI3K/Akt pathway component modulated by negative regulators | Survival signaling in endothelial cells |
| AKT1 | Central kinase in VEGF survival signaling, subject to inhibition | Phosphorylation readouts |
| HIF1A | Oxygen-sensitive transcription factor affecting VEGF feedback | Hypoxia and infarction models |
| IGFBP5 | Probable modulator of VEGF-related pathways in cancer | Kidney cancer research |
| VEGFA | Primary ligand whose response is negatively regulated | Ligand stimulation assays |
| VEGFB | Ligand whose cellular response is negatively regulated | Endothelial metabolism studies |
| KDR | VEGFR2 receptor; its activity is a target of negative regulation | Receptor internalization assays |
| FLT1 | VEGFR1 decoy receptor can sequester VEGF | Negative regulation via ligand trapping |
| NRP1 | Co-receptor modulating VEGF signaling | Complex formation studies |
| ADORA2B | Adenosine receptor inducing HIF-1α in stromal cells | Myocardial infarction models |
| TNF | Inflammatory cytokine influencing VEGF responses | Anti-inflammatory diet studies |
| IL6 | Inflammatory mediator linked to VEGF signaling | Inflammation models |
| ACTIVIN_A | Stimulates VEGF gene transcription in hepatocellular carcinoma | Liver cancer models |
| RANKL | Regulates endothelial survival via PI3K/Akt | Survival assays |
| HSPA1A | Stress protein potentially modulating VEGF signaling | Hypothermia neuroprotection |
| CASP3 | Apoptosis effector downstream of VEGF withdrawal | Cell death assays |
How Is negative regulation of cellular response to vascular endothelial growth factor stimulus Regulated?
GO:1902548 is regulated at multiple levels. Receptor availability is controlled by internalization and decoy receptors like FLT1. Downstream, Rho kinase and PI3K/Akt phosphatases set signaling thresholds. Hypoxia and HIF-1α provide transcriptional feedback, with adenosine-A2B receptor signaling inducing HIF-1α even under normoxia in epicardial stromal cells. Systemic factors such as anti-inflammatory diets and IGFBP5 expression further modulate the response.
negative regulation of cellular response to vascular endothelial growth factor stimulus and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| IGFBP5 | Kidney renal papillary renal cell carcinoma | Knockout in renal cancer cell lines |
| ACTIVIN_A | Hepatocellular carcinoma | Overexpression in HepG2 cells |
| ADORA2B | Myocardial infarction | Knockout in epicardial stromal cells |
| RANKL | Endothelial survival in inflammation | Point mutation in PI3K/Akt binding site |
| HIF1A | Ischemia-reperfusion injury | Knock-in of hypoxia-stable mutant |
Cancer and tumor angiogenesis
Loss of negative regulation of VEGF responses can promote tumor angiogenesis. IGFBP5 is a probable target in kidney renal papillary renal cell carcinoma, suggesting that its dysregulation may enhance VEGF-driven tumor growth. Activin A stimulates VEGF gene transcription in hepatocellular carcinoma cells, and failure to counter this signal may support liver cancer progression.
Cardiovascular and ischemic injury
After myocardial infarction, adenosine-A2B receptor signaling induces HIF-1α in epicardial stromal cells, which may modulate VEGF responses and affect cardiac repair. In skeletal muscle, HIF-1 and exercise influence VEGF-related adaptations, and impaired negative regulation could contribute to maladaptive angiogenesis.
Neuroprotection and ischemia-reperfusion
Mild hypothermia protects the hippocampus from global cerebral ischemia-reperfusion injury, and proteome profiling reveals changes in proteins that may intersect with VEGF negative regulation. This suggests that modulating GO:1902548 could be neuroprotective.
Inflammation and metabolic disease
Anti-inflammatory diets may reduce VEGF-driven inflammatory signaling, indirectly enhancing negative regulation of VEGF responses. RANKL regulates endothelial survival through PI3K/Akt, and its dysregulation can alter VEGF-dependent vascular permeability in inflammatory conditions.
From negative regulation of cellular response to vascular endothelial growth factor stimulus-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X negatively regulate VEGF-induced migration? | CRISPR knockout in HUVECs followed by chemotaxis assay |
| Does a point mutation in PI3K/Akt alter VEGF survival signaling? | Knock-in of phospho-mutant in endothelial cells |
| Does overexpression of IGFBP5 reduce VEGF response in cancer? | Doxycycline-inducible overexpression in renal carcinoma cells |
| Does HIF-1α feedback require adenosine-A2B receptor? | Knockout of ADORA2B in epicardial stromal cells |
| Does anti-inflammatory diet modulate VEGF response? | Mouse model with dietary intervention and VEGF readouts |
| Does RANKL regulate endothelial survival via PI3K/Akt? | Knockdown or knockout of RANKL in endothelial cells |
How to Study the negative regulation of cellular response to vascular endothelial growth factor stimulus Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout screen | Gene essentiality for VEGF response | Identify negative regulators |
| Phospho-Akt Western blot | PI3K/Akt pathway activity | Survival signaling |
| Rho kinase activity assay | Cytoskeletal signaling | Chemotaxis |
| RNA-seq | Transcriptional changes | VEGF target genes |
| Proteomics | Protein abundance changes | Hypothermia neuroprotection |
| Tube formation assay | Angiogenesis in vitro | Endothelial function |
| Chemotaxis assay | Directed cell migration | VEGF response |
| Immunofluorescence | Receptor localization | Internalization studies |
CRISPR knockout screens
Genome-wide CRISPR knockout screens can identify genes whose loss enhances or suppresses VEGF-induced phenotypes, directly mapping negative regulators within GO:1902548. Such screens in endothelial cells under VEGF stimulation reveal candidate brakes.
Phosphoproteomics and signaling assays
Phosphoproteomics can quantify changes in PI3K/Akt and Rho kinase pathways after VEGF stimulation, identifying negative feedback nodes. Western blotting for phospho-Akt and phospho-VEGFR2 is a standard readout.
Transcriptomics and proteomics
RNA-seq and proteome profiling reveal transcriptional and protein-level changes in VEGF response genes. For example, proteome profiling of hippocampus after hypothermia identified proteins linked to VEGF regulation. Anti-inflammatory diet studies also use transcriptomic endpoints.
Imaging and functional assays
Live-cell imaging of receptor internalization, tube formation assays, and chemotaxis assays measure the functional output of negative regulation. These methods are essential for validating CRISPR perturbations.
How CRISPR Can Be Used to Study GO:1902548 negative regulation of cellular response to vascular endothelial growth factor stimulus
Knockout
CRISPR knockout of candidate negative regulators such as RHOA or ADORA2B can test whether their loss enhances VEGF-induced migration or survival. Knockout models are ideal for loss-of-function studies of GO:1902548.
Point Mutation
Point mutations can be introduced into phosphorylation sites of AKT1 or RANKL to dissect specific signaling residues required for negative regulation. This approach avoids confounding effects of complete protein loss.
Knock-in
Knock-in of tagged or mutant alleles, such as hypoxia-stable HIF1A, allows tracking of protein localization and stability under VEGF stimulation. Knock-in reporters can quantify negative regulation in real time.
Overexpression
Overexpression of IGFBP5 or other brakes can suppress VEGF responses in cancer cells, validating their negative regulatory role. Inducible overexpression systems provide temporal control.
How EDITGENE Supports negative regulation of cellular response to vascular endothelial growth factor stimulus Research
Researchers studying negative regulation of cellular response to vascular endothelial growth factor stimulus-related genes often need to determine whether a candidate gene is causally involved in dampening VEGF signaling, and CRISPR-based models provide the most direct evidence.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of cellular response to vascular endothelial growth factor stimulus research.
Frequently Asked Questions About negative regulation of cellular response to vascular endothelial growth factor stimulus
What is GO:1902548?
GO:1902548 is the Gene Ontology term for any process that stops, prevents, or reduces the cellular response to VEGF, VEGF-A, or VEGF-B stimulation.
What genes are involved in negative regulation of VEGF response?
Key genes include RHOA, PIK3CA, AKT1, HIF1A, IGFBP5, ADORA2B, and RANKL, among others.
How does Rho kinase inhibit VEGF signaling?
Rho kinase activity downstream of G(ialpha2) modulates VEGF-induced endothelial chemotaxis, effectively dampening the response.
What is the role of HIF-1α in VEGF negative regulation?
HIF-1α can be induced under normoxia by adenosine-A2B receptor signaling and provides feedback that modulates VEGF responses.
Can CRISPR knockout help study this term?
Yes, CRISPR knockout of candidate genes such as ADORA2B or RHOA can reveal their role in negative regulation of VEGF signaling.
What diseases are linked to defective VEGF negative regulation?
Cancer, myocardial infarction, ischemia-reperfusion injury, and inflammatory diseases are linked to dysregulation of this process.
How is IGFBP5 related to VEGF signaling?
IGFBP5 is a probable target in kidney renal papillary renal cell carcinoma and may modulate VEGF-related pathways.
What methods measure negative regulation of VEGF response?
CRISPR screens, phospho-Akt Western blots, RNA-seq, proteomics, and chemotaxis assays are commonly used.
Does anti-inflammatory diet affect VEGF response?
Anti-inflammatory diets may reduce VEGF-driven inflammatory signaling, indirectly contributing to negative regulation.
What model systems are used to study GO:1902548?
Endothelial cells, cancer cell lines, and mouse models of infarction or ischemia are commonly used.
Conclusion
GO:1902548 represents a critical braking mechanism that keeps VEGF signaling in check, with profound implications for angiogenesis, cancer, and cardiovascular disease. Understanding its genetic and molecular players through CRISPR-based models will accelerate therapeutic discovery. EDITGENE offers comprehensive services to dissect this pathway in relevant cell models.
References
- 1. Scheiber A et al.. 2026. Anti-Inflammatory Diets.. PMID: 37983365
- 2. Lindholm ME et al.. 2016. Skeletal muscle hypoxia-inducible factor-1 and exercise.. Exp Physiol 101(1):28-32 PMID: 26391197
- 3. Wang S et al.. 2019. Insulin-Like Growth Factor Binding Protein 5-A Probable Target of Kidney Renal Papillary Renal Cell Carcinoma.. Biomed Res Int 2019:3210324 PMID: 31886201
- 4. Wagner K et al.. 2004. Activin A stimulates vascular endothelial growth factor gene transcription in human hepatocellular carcinoma cells.. Gastroenterology 126(7):1828-43 PMID: 15188178
- 5. Liu F et al.. 2001. Differential regulation of sphingosine-1-phosphate- and VEGF-induced endothelial cell chemotaxis. Involvement of G(ialpha2)-linked Rho kinase activity.. Am J Respir Cell Mol Biol 24(6):711-9 PMID: 11415936
- 6. Hesse J et al.. 2021. Normoxic induction of HIF-1α by adenosine-A(2B) R signaling in epicardial stromal cells formed after myocardial infarction.. FASEB J 35(5):e21517 PMID: 33913581
- 7. Kim HH et al.. 2003. RANKL regulates endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway.. FASEB J 17(14):2163-5 PMID: 14500543
- 8. Wang J et al.. 2023. Proteome profiling of hippocampus reveals the neuroprotective effect of mild hypothermia on global cerebral ischemia-reperfusion injury in rats.. Sci Rep 13(1):14450 PMID: 37660166
