GO:1900748 positive regulation of vascular endothelial growth factor signaling pathway: Angiogenesis Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1900748 describes any process that activates or increases the frequency, rate or extent of vascular endothelial growth factor (VEGF) signaling.
• VEGF signaling is initiated by ligand binding to VEGFR1 (FLT1) and VEGFR2 (KDR), with VEGFR2 driving most pro-angiogenic outputs.
• Positive regulation of VEGF signaling is essential for physiological angiogenesis, vascular permeability, and endothelial survival.
• In tumors, VEGF-A can suppress CD8+ T cell effector function and modulate immune checkpoint expression, linking this GO term to cancer immunotherapy.
• VEGF signaling is a validated therapeutic target in iodine-refractory differentiated thyroid carcinoma and other malignancies.
• CRISPR knockout, knock-in, and overexpression models enable causal dissection of genes that positively regulate VEGF signaling.
Description
GO:1900748, positive regulation of vascular endothelial growth factor signaling pathway, is a biological process ontology term that captures any molecular event that activates or increases the frequency, rate, or extent of VEGF signaling. VEGF signaling is a central regulator of angiogenesis, vascular permeability, and endothelial cell survival, and its dysregulation contributes to cancer, diabetic kidney disease, and other pathologies. Understanding which genes and mechanisms positively regulate this pathway is therefore critical for both basic vascular biology and therapeutic development. This article synthesizes authoritative QuickGO annotation data with verified PubMed literature to provide a research-grade overview of GO:1900748, including its definition, core mechanisms, key genes, disease relevance, and experimental models. The content is designed for researchers, clinicians, and AI retrieval systems seeking accurate, citation-backed information on VEGF signaling positive regulation.
positive regulation of vascular endothelial growth factor signaling pathway At A Glance
| GO ID | GO:1900748 |
|---|---|
| GO term | positive regulation of vascular endothelial growth factor signaling pathway |
| Ontology | biological_process |
| Synonym | activation of VEGF signaling; upregulation of VEGF-activated signaling pathway; positive regulation of VEGF signaling |
| Major function | Enhances VEGF ligand-receptor signaling to promote angiogenesis, vascular permeability, and endothelial survival |
| Upstream regulators | VEGF-A, VEGF-B, VEGFR1 (FLT1), VEGFR2 (KDR), Neuropilin-1 (NRP1) |
| Downstream effectors | ETS2, NNMT, CD8+ T cell checkpoints |
| Disease relevance | Cancer, diabetic kidney disease, thyroid carcinoma, retinal vascular disorders |
| Research methods | CRISPR KO/KI, scRNA-seq, Ribo-seq, proteomics, imaging |
What Is GO:1900748?
GO:1900748 is defined by QuickGO as any process that activates or increases the frequency, rate or extent of vascular endothelial growth factor signaling pathway. In practical terms, it encompasses molecular events that enhance VEGF ligand availability, receptor activation, downstream kinase signaling, or transcriptional outputs that amplify VEGF pathway activity. This term is a child of positive regulation of signal transduction and is specific to the VEGF signaling cascade, distinguishing it from general angiogenesis or endothelial cell proliferation terms.
Why Is positive regulation of vascular endothelial growth factor signaling pathway Important in Cell Biology?
Positive regulation of VEGF signaling is a fundamental process in vascular biology because it controls the balance between normal angiogenesis and pathological vascular growth. In cancer, tumor cells and cancer-associated fibroblasts can upregulate VEGF-A via epigenetic mechanisms such as NNMT-mediated ETS2 regulation, driving pro-angiogenic phenotypes and immune evasion. In diabetic kidney disease, VEGF-B-mediated fatty acid flux in the adipose-kidney axis contributes to lipotoxicity, highlighting metabolic crosstalk with VEGF signaling. Neuropilin-1 controls vascular permeability through juxtacrine regulation of endothelial adherens junctions, further demonstrating the importance of positive regulation in vascular barrier function. Therapeutically, targeting VEGF pathway components has shown benefit in iodine-refractory differentiated thyroid carcinoma, underscoring the clinical relevance of this GO term.
• Controls physiological angiogenesis during development and tissue repair.
• Regulates vascular permeability through endothelial adherens junctions.
• Modulates immune checkpoint expression on CD8+ T cells in tumors.
• Contributes to diabetic kidney disease via VEGF-B-mediated lipotoxicity.
• Drives pro-angiogenic phenotypes in cancer-associated fibroblasts.
• Serves as a therapeutic target in thyroid carcinoma and other cancers.
• Mediates response to anti-angiogenic therapy combined with immunotherapy in NSCLC.
• Involved in retinoic acid pathway regulation of VEGF in ovine amnion.
• Provides mechanistic insights for CRISPR-based functional genomics.
• Enables development of targeted therapies for vascular and metabolic diseases.
What Happens During positive regulation of vascular endothelial growth factor signaling pathway?
Ligand Availability and Receptor Binding
In simple terms: VEGF proteins are made available and bind to their receptors on the cell surface.
Positive regulation begins with increased VEGF ligand availability, including VEGF-A and VEGF-B, which bind to VEGFR1 (FLT1) and VEGFR2 (KDR) on endothelial cells. Neuropilin-1 (NRP1) acts as a co-receptor that enhances VEGF binding and signaling specificity. In cancer-associated fibroblasts, NNMT epigenetically regulates the ETS2/VEGFA axis, increasing VEGFA expression and secretion. Retinoic acid pathway components can also regulate VEGF expression in ovine amnion, demonstrating tissue-specific control.
Receptor Activation and Downstream Kinase Signaling
In simple terms: Once VEGF binds, the receptors activate a cascade of signaling proteins inside the cell.
VEGFR2 activation leads to autophosphorylation and recruitment of downstream effectors that drive endothelial proliferation, migration, and survival. VEGFR1 can modulate signaling by acting as a decoy or by transmitting distinct signals depending on context. Positive regulation of this pathway involves enhancing receptor kinase activity, preventing dephosphorylation, or increasing receptor surface expression. In non-small cell lung cancer, VEGF signaling mediates the response to neoadjuvant anlotinib combined with PD-1 blockade, indicating that downstream kinase activity is clinically actionable.
Endothelial Cell Responses: Permeability and Adherens Junctions
In simple terms: VEGF signaling makes blood vessels leakier and promotes new vessel growth.
Neuropilin-1 controls vascular permeability through juxtacrine regulation of endothelial adherens junctions, a key downstream output of positive VEGF signaling. VEGF-A increases vascular permeability, which is essential for angiogenesis but also contributes to edema and inflammation. Positive regulation of VEGF signaling can therefore enhance both physiological and pathological vascular permeability.
Immune Modulation and Tumor Microenvironment
In simple terms: VEGF signaling can change how immune cells behave in tumors.
VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors, linking positive VEGF signaling to immune evasion. In non-small cell lung cancer, VEGF signaling mediates the response to combined anti-angiogenic and immunotherapy, suggesting that positive regulation influences treatment outcomes. Cancer-associated fibroblasts with high NNMT activity switch to a proangiogenic phenotype via the ETS2/VEGFA axis, further remodeling the tumor microenvironment.
Metabolic Crosstalk: VEGF-B and Lipotoxicity
In simple terms: VEGF-B can affect fat metabolism in organs like the kidney.
VEGF-B-mediated fatty acid flux in the adipose-kidney axis contributes to lipotoxicity in diabetic kidney disease, demonstrating that positive regulation of VEGF signaling extends beyond classical angiogenesis. This metabolic role highlights the need to study GO:1900748 in the context of metabolic disorders.
Key Genes Involved in GO:1900748 positive regulation of vascular endothelial growth factor signaling pathway
The following genes and proteins are central to positive regulation of VEGF signaling, based on verified literature and QuickGO annotations.
| Gene | Major Role | Research Relevance |
|---|---|---|
| VEGFA | Primary ligand for VEGFR2; drives angiogenesis and permeability | Target in cancer and diabetic kidney disease |
| VEGFB | Ligand for VEGFR1; regulates fatty acid flux and lipotoxicity | Implicated in diabetic kidney disease |
| FLT1 (VEGFR1) | Receptor that modulates VEGF signaling; can act as decoy | Differential roles in angiogenesis |
| KDR (VEGFR2) | Major pro-angiogenic receptor; activates downstream kinases | Central to VEGF signaling positive regulation |
| NRP1 | Co-receptor enhancing VEGF binding; controls vascular permeability | Regulates adherens junctions |
| ETS2 | Transcription factor regulating VEGFA expression | Epigenetically regulated by NNMT in cancer-associated fibroblasts |
| NNMT | Epigenetic regulator of ETS2/VEGFA axis | Switches proangiogenic phenotype in cancer-associated fibroblasts |
| CD8+ T cells (checkpoint genes) | Immune effectors modulated by VEGF-A | VEGF-A modulates inhibitory checkpoints |
| PD-1/PD-L1 pathway | Immune checkpoint influenced by VEGF signaling | Response to anlotinib plus PD-1 blockade in NSCLC |
| Retinoic acid pathway genes | Regulate VEGF expression in amnion | Ovine amnion model |
| Anlotinib targets | Tyrosine kinase inhibitors affecting VEGF signaling | Neoadjuvant therapy in NSCLC |
| Thyroid carcinoma drivers | VEGF pathway components in DTC | Targeting VEGF pathway in iodine-refractory DTC |
| Endothelial adherens junction proteins | Maintain vascular barrier; regulated by NRP1 | Vascular permeability studies |
| Fatty acid transport proteins | Mediate VEGF-B effects on lipid flux | Adipose-kidney axis in diabetes |
| Hypoxia-inducible factors (HIFs) | Upstream regulators of VEGFA transcription | General VEGF regulation |
| Neuropilin co-receptors | Modulate VEGF signaling specificity | Juxtacrine regulation |
| VEGFR-associated phosphatases | Negatively regulate VEGF signaling | Potential targets for positive regulation |
| Immune checkpoint molecules | Modulated by VEGF-A in tumors | CD8+ T cell exhaustion |
How Is positive regulation of vascular endothelial growth factor signaling pathway Regulated?
Positive regulation of VEGF signaling is controlled at multiple levels. Transcriptional regulation of VEGFA by ETS2 and epigenetic modifiers such as NNMT can increase ligand production. Retinoic acid pathway components regulate VEGF expression in ovine amnion, indicating hormonal control. Neuropilin-1 modulates receptor complex formation and downstream signaling strength. At the receptor level, VEGFR1 and VEGFR2 have differential roles, with VEGFR2 being the primary positive driver. Additionally, metabolic signals such as VEGF-B-mediated fatty acid flux can influence pathway activity in diabetic kidney disease. Immune checkpoint molecules on CD8+ T cells are modulated by VEGF-A, providing a feedback loop between VEGF signaling and adaptive immunity.
positive regulation of vascular endothelial growth factor signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| VEGFA | Tumor angiogenesis and immune evasion | CRISPR KO in cancer cell lines; syngeneic mouse models |
| VEGFB | Diabetic kidney disease and lipotoxicity | Adipose-specific KO mice; kidney organoids |
| NRP1 | Vascular permeability and edema | Endothelial-specific KO; in vitro permeability assays |
| NNMT | Cancer-associated fibroblast proangiogenic switch | CRISPR KO in fibroblasts; co-culture with endothelial cells |
| KDR (VEGFR2) | Angiogenesis and cancer | Kinase-dead knock-in; xenograft models |
Cancer and Tumor Angiogenesis
Positive regulation of VEGF signaling is a hallmark of tumor angiogenesis. Cancer-associated fibroblasts with high NNMT activity epigenetically regulate the ETS2/VEGFA axis, switching to a proangiogenic phenotype that supports tumor growth. VEGF-A modulates inhibitory checkpoints on CD8+ T cells, contributing to immune evasion. In non-small cell lung cancer, VEGF signaling mediates the response to neoadjuvant anlotinib combined with PD-1 blockade therapy, highlighting the clinical importance of this pathway. Targeting VEGF signaling has shown benefit in iodine-refractory differentiated thyroid carcinoma.
Diabetic Kidney Disease
VEGF-B-mediated fatty acid flux in the adipose-kidney axis contributes to lipotoxicity in diabetic kidney disease. This suggests that positive regulation of VEGF signaling can have metabolic consequences beyond classical angiogenesis, and that targeting VEGF-B may be therapeutically relevant in diabetes.
Vascular Permeability and Edema
Neuropilin-1 controls vascular permeability through juxtacrine regulation of endothelial adherens junctions. Positive regulation of VEGF signaling can therefore exacerbate vascular leak in conditions such as inflammation, sepsis, and retinal edema.
Thyroid Carcinoma
Targeting the VEGF pathway in iodine-refractory differentiated thyroid carcinoma has been explored from bench to bedside, demonstrating that positive regulation of VEGF signaling is a clinically actionable process in this disease.
From positive regulation of vascular endothelial growth factor signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X positively regulate VEGF signaling? | CRISPR knockout in endothelial cells followed by VEGF-induced signaling assays |
| Does a specific point mutation in VEGFR2 alter kinase activity? | Point-mutation knock-in via CRISPR in cell lines |
| Can a tagged VEGFA be used to track secretion? | Knock-in of fluorescent or epitope tag at endogenous VEGFA locus |
| Does overexpression of NNMT increase VEGFA and angiogenesis? | Overexpression cell models and co-culture with endothelial cells |
| What is the role of NRP1 in vascular permeability? | Endothelial-specific knockout or knock-in of NRP1 mutants |
| How does VEGF-B affect lipid flux in kidney? | Adipose-kidney axis organoid or mouse models with VEGF-B KO |
How to Study the positive regulation of vascular endothelial growth factor signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout | Loss-of-function effects on VEGF signaling | Identify positive regulators in endothelial cells |
| CRISPR knock-in | Tagged or mutant protein expression | Track VEGFA secretion or VEGFR2 kinase activity |
| RNA-seq | Transcriptional changes in VEGF pathway genes | Response to anti-angiogenic therapy |
| scRNA-seq | Single-cell expression heterogeneity | Tumor microenvironment analysis |
| Phosphoproteomics | Receptor and downstream phosphorylation | VEGFR2 activation status |
| Permeability assay | Endothelial barrier function | NRP1-mediated adherens junction regulation |
| Intravital microscopy | In vivo angiogenesis and vascular leak | Tumor models |
| Co-culture assays | Cell-cell interactions in angiogenesis | Cancer-associated fibroblast-endothelial crosstalk |
CRISPR-Based Functional Genomics
CRISPR knockout, knock-in, and overexpression screens can identify genes that positively regulate VEGF signaling. For example, scRNA-seq revealed that VEGF signaling mediates response to anlotinib plus PD-1 blockade in NSCLC, and CRISPR screens could validate candidate regulators. NNMT was shown to regulate the ETS2/VEGFA axis, and CRISPR KO of NNMT can reverse the proangiogenic phenotype.
Transcriptomics and Single-Cell Analysis
RNA-seq and scRNA-seq measure changes in VEGF pathway gene expression. scRNA-seq has been used to dissect VEGF signaling in non-small cell lung cancer under therapy. Retinoic acid pathway regulation of VEGF in ovine amnion was studied using expression profiling.
Proteomics and Phosphoproteomics
Mass spectrometry-based proteomics can quantify VEGFR2 phosphorylation and downstream signaling events. Differential roles of VEGFR1 and VEGFR2 in angiogenesis have been characterized using biochemical assays. Neuropilin-1 regulation of adherens junctions can be studied by phosphoproteomics of endothelial cells.
Imaging and Permeability Assays
Live-cell imaging and permeability assays measure VEGF-induced vascular leak. Neuropilin-1 controls vascular permeability through juxtacrine regulation, which can be visualized using endothelial monolayer assays. Tumor angiogenesis can be imaged in vivo using intravital microscopy.
How CRISPR Can Be Used to Study GO:1900748 positive regulation of vascular endothelial growth factor signaling pathway
Knockout
CRISPR knockout of candidate genes such as NNMT, VEGFA, or NRP1 can determine whether they are required for positive regulation of VEGF signaling. For example, NNMT knockout reverses the proangiogenic phenotype of cancer-associated fibroblasts by disrupting the ETS2/VEGFA axis. Endothelial-specific knockout of NRP1 can reveal its role in vascular permeability.
Point Mutation
Point mutations in VEGFR2 or VEGFA can be introduced to study kinase activity or ligand-receptor affinity. Such models help dissect the differential roles of VEGFR1 and VEGFR2 in angiogenesis. Point mutations in NRP1 can identify domains required for adherens junction regulation.
Knock-in
Knock-in of fluorescent or epitope tags at endogenous loci allows tracking of VEGFA or VEGFR2 in live cells. This is useful for studying secretion, trafficking, and receptor internalization during positive regulation of VEGF signaling. Tagged knock-in models can also be used for proteomic pull-downs.
Overexpression
Overexpression of VEGFA, NNMT, or ETS2 can test sufficiency for activating VEGF signaling. Overexpression models are valuable for studying cancer-associated fibroblast-driven angiogenesis. Inducible overexpression systems allow temporal control of pathway activation.
How EDITGENE Supports positive regulation of vascular endothelial growth factor signaling pathway Research
Researchers studying positive regulation of vascular endothelial growth factor signaling pathway-related genes often need to determine whether a candidate gene is causally involved in enhancing VEGF signaling, and CRISPR-based models provide the most direct approach. EDITGENE offers a comprehensive suite of services to support such studies, from knockout and point-mutation cell lines to overexpression and library screening.
Contact EDITGENE today to design your custom CRISPR model for positive regulation of vascular endothelial growth factor signaling pathway research.
Frequently Asked Questions About positive regulation of vascular endothelial growth factor signaling pathway
What is GO:1900748?
GO:1900748 is the Gene Ontology term for positive regulation of vascular endothelial growth factor signaling pathway, describing any process that activates or increases VEGF signaling.
What genes are involved in positive regulation of VEGF signaling?
Key genes include VEGFA, VEGFB, FLT1 (VEGFR1), KDR (VEGFR2), NRP1, ETS2, and NNMT.
How does VEGF signaling promote angiogenesis?
VEGF ligands bind VEGFR2, activating downstream kinases that drive endothelial proliferation, migration, and survival.
What diseases are associated with VEGF signaling?
Cancer, diabetic kidney disease, thyroid carcinoma, and vascular permeability disorders.
How can I study positive regulation of VEGF signaling with CRISPR?
Use CRISPR knockout, knock-in, or overexpression to test candidate genes in endothelial or cancer cell models.
What is the role of neuropilin-1 in VEGF signaling?
Neuropilin-1 acts as a co-receptor that enhances VEGF binding and controls vascular permeability through adherens junctions.
Does VEGF-A affect immune checkpoints?
Yes, VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors.
What is the link between VEGF-B and diabetic kidney disease?
VEGF-B-mediated fatty acid flux in the adipose-kidney axis contributes to lipotoxicity in diabetic kidney disease.
How does NNMT regulate VEGF signaling?
NNMT epigenetically regulates the ETS2/VEGFA axis, switching cancer-associated fibroblasts to a proangiogenic phenotype.
What methods are used to measure VEGF signaling activity?
Phosphoproteomics, RNA-seq, scRNA-seq, permeability assays, and imaging are commonly used.
Conclusion
GO:1900748, positive regulation of vascular endothelial growth factor signaling pathway, is a critical biological process that governs angiogenesis, vascular permeability, and immune modulation. Its dysregulation is implicated in cancer, diabetic kidney disease, and thyroid carcinoma, making it a high-value target for therapeutic intervention. CRISPR-based models, including knockout, knock-in, and overexpression, provide powerful tools to dissect the causal roles of individual genes in this pathway. EDITGENE offers comprehensive services to accelerate such research, from custom cell line generation to library screening and bioinformatics analysis.
References
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- 2. Cheung CY et al.. 2019. Retinoic Acid Pathway Regulation of Vascular Endothelial Growth Factor in Ovine Amnion.. Reprod Sci 26(10):1351-1359 PMID: 29587617
- 3. Pal S et al.. 2024. Neuropilin-1 controls vascular permeability through juxtacrine regulation of endothelial adherens junctions.. Angiogenesis 28(1):7 PMID: 39668325
- 4. Voron T et al.. 2015. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors.. J Exp Med 212(2):139-48 PMID: 25601652
- 5. Huang Z et al.. 2025. scRNA-seq reveals that VEGF signaling mediates the response to neoadjuvant anlotinib combined with PD-1 blockade therapy in non-small cell lung cancer.. J Transl Med 23(1):478 PMID: 40281576
- 6. Shibuya M. 2006. Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis.. J Biochem Mol Biol 39(5):469-78 PMID: 17002866
- 7. Wang X et al.. 2024. NNMT switches the proangiogenic phenotype of cancer-associated fibroblasts via epigenetically regulating ETS2/VEGFA axis.. Oncogene 43(35):2647-2660 PMID: 39069579
- 8. Abdel-Rahman O. 2015. Targeting vascular endothelial growth factor (VEGF) pathway in iodine-refractory differentiated thyroid carcinoma (DTC): from bench to bedside.. Crit Rev Oncol Hematol 94(1):45-54 PMID: 25560732
