GO:0010575 positive regulation of vascular endothelial growth factor production: Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0010575 describes any biological process that increases the frequency, rate, or extent of vascular endothelial growth factor (VEGF) production.
• VEGF production is positively regulated at transcriptional, post-transcriptional, and microenvironmental levels, with hypoxia and inflammatory signals as key drivers.
• Key positive regulators include HIF-1α, NF-κB, STAT3, and growth factors such as midkine, which upregulate VEGFA expression.
• Dysregulated VEGF production contributes to cancer angiogenesis, psoriasis, endometriosis, and age-related macular degeneration.
• CRISPR knockout, knock-in, and overexpression models are essential to dissect causal roles of candidate regulators in VEGF production.
• Targeting positive regulators of VEGF production is a therapeutic strategy in oncology and ocular neovascular diseases.
Description
GO:0010575, positive regulation of vascular endothelial growth factor production, is a biological process term that encompasses any mechanism that increases the synthesis or release of vascular endothelial growth factor (VEGF). VEGF is a secreted cytokine critical for angiogenesis, vascular permeability, and endothelial cell survival, and its production is tightly controlled under physiological conditions. Disruption of this regulation leads to pathological angiogenesis in tumors, chronic inflammatory diseases, and ocular disorders. Understanding the positive regulators of VEGF production is therefore central to both developmental biology and disease research.
positive regulation of vascular endothelial growth factor production At A Glance
| GO ID | GO:0010575 |
|---|---|
| GO term | positive regulation of vascular endothelial growth factor production |
| Ontology | biological_process |
| Synonym | None |
| Major function | Upregulation of VEGF synthesis and secretion |
| Definition | Any process that increases or activates the frequency, rate, or extent of production of vascular endothelial growth factor. |
| Related processes | Angiogenesis, hypoxia response, inflammatory signaling |
| Key regulators | HIF-1α, NF-κB, STAT3, midkine, TGF-β1 |
What Is GO:0010575?
According to the Gene Ontology, GO:0010575 refers to any process that increases or activates the frequency, rate, or extent of production of vascular endothelial growth factor. This includes transcriptional activation of the VEGFA gene, enhanced mRNA stability, increased translation, and facilitated secretion of the VEGF protein. The term is distinct from VEGF signaling, which describes the downstream response to VEGF, whereas GO:0010575 specifically covers the upstream events that elevate VEGF levels.
Why Is positive regulation of vascular endothelial growth factor production Important in Cell Biology?
Positive regulation of VEGF production is a central node in angiogenesis and vascular pathology. In cancer, tumor cells and stromal cells upregulate VEGF to promote neovascularization, supporting tumor growth and metastasis. In chronic inflammatory diseases such as psoriasis and endometriosis, excessive VEGF production drives aberrant vascular permeability and lesion formation. In age-related macular degeneration, metabolic and epigenetic changes enhance VEGF production, leading to choroidal neovascularization. Therefore, understanding the positive regulators of VEGF production offers therapeutic opportunities to modulate angiogenesis in diverse diseases.
• Drives tumor angiogenesis and metastasis in multiple cancers.
• Mediates hypoxia-induced vascular remodeling in ischemic tissues.
• Contributes to inflammatory skin diseases such as psoriasis.
• Plays a role in endometriosis-associated angiogenesis and inflammation.
• Involved in age-related macular degeneration through metabolic and epigenetic regulation.
• Regulates placental vascular development via pericyte function.
• Modulates scar formation and wound healing.
• Serves as a therapeutic target for anti-angiogenic therapies.
• Provides a model for studying gene-environment interactions in vascular biology.
• Enables CRISPR-based dissection of causal regulatory networks.
What Happens During positive regulation of vascular endothelial growth factor production?
Transcriptional Activation of VEGFA
In simple terms: The cell receives a signal to make more VEGF, so it turns on the VEGFA gene.
Positive regulation of VEGF production often begins with transcriptional activation of the VEGFA gene. Hypoxia-inducible factor 1-alpha (HIF-1α) binds to hypoxia response elements in the VEGFA promoter under low oxygen conditions, increasing transcription. Inflammatory cytokines such as TNF-α and IL-1β activate NF-κB and STAT3, which also promote VEGFA transcription. Midkine, a heparin-binding growth factor, has been shown to upregulate VEGFA expression in psoriasis, further illustrating transcriptional control.
Post-transcriptional and Translational Control
In simple terms: After the gene is turned on, the cell can still make more or less VEGF protein by controlling the mRNA.
VEGF production is also regulated post-transcriptionally. Hypoxia and inflammatory signals can stabilize VEGFA mRNA, increasing its half-life and translational efficiency. MicroRNAs and RNA-binding proteins can either enhance or repress VEGF translation, and their dysregulation contributes to pathological VEGF overproduction. In age-related macular degeneration, histone lactylation and ALKBH3-mediated glycolysis have been linked to feedback regulation of VEGF production, highlighting epigenetic and metabolic control.
Microenvironmental and Cellular Sources
In simple terms: Many different cell types in the tissue can produce VEGF, and their interactions boost overall production.
VEGF is produced by diverse cell types including tumor cells, macrophages, fibroblasts, endothelial cells, and pericytes. In the tumor microenvironment, cancer cells and immune cells crosstalk to amplify VEGF production. Placental pericytes regulate VEGF production through TGF-β1 signaling, demonstrating tissue-specific control. In endometriosis, hypoxic and inflammatory microenvironments stimulate VEGF production from endometrial and immune cells.
Feedback and Amplification Loops
In simple terms: Once VEGF is made, it can trigger more signals that lead to even more VEGF production.
Positive regulation of VEGF production often involves feed-forward loops. VEGF secreted by tumor cells can act on endothelial cells to release additional growth factors and cytokines, further stimulating VEGF production. In psoriasis, midkine-induced VEGFA can promote inflammation, which in turn enhances VEGF production. Such amplification loops are critical in chronic diseases and are targets for therapeutic intervention.
Key Genes Involved in GO:0010575 positive regulation of vascular endothelial growth factor production
The following genes and proteins are key players in the positive regulation of vascular endothelial growth factor production, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| VEGFA | Encodes VEGF-A, the primary effector of angiogenesis | Central to all studies of VEGF production |
| HIF1A | Hypoxia-inducible transcription factor; activates VEGFA transcription | Master regulator under hypoxia |
| NFKB1 | Transcription factor mediating inflammatory VEGF induction | Links inflammation to VEGF production |
| STAT3 | Transcription factor activated by cytokines; promotes VEGFA expression | Involved in tumor and inflammatory angiogenesis |
| MDK | Midkine, a growth factor that upregulates VEGFA | Implicated in psoriasis and cancer |
| TGFB1 | Transforming growth factor beta-1; regulates pericyte function and VEGF | Placental and vascular biology |
| ALKBH3 | RNA demethylase; linked to glycolysis and VEGF regulation | Age-related macular degeneration |
| EPAS1 | HIF-2α; regulates VEGF in endothelial cells | Angiogenesis and tumor progression |
| PGF | Placental growth factor; modulates VEGF signaling | Endometriosis and cancer |
| KDR | VEGFR-2; mediates VEGF signaling but also feedback on production | Therapeutic target |
| FLT1 | VEGFR-1; modulates VEGF availability | Angiogenesis regulation |
| IL6 | Cytokine that induces VEGF via STAT3 | Inflammatory angiogenesis |
| TNF | TNF-α; activates NF-κB and VEGF production | Inflammation and cancer |
| PTGS2 | COX-2; prostaglandin synthesis linked to VEGF | Inflammation and tumor angiogenesis |
| SP1 | Transcription factor binding VEGFA promoter | Basal and induced VEGF expression |
| EGR1 | Early growth response 1; regulates VEGFA transcription | Hypoxia and injury responses |
| HIF3A | Inhibitory PAS domain protein; can modulate HIF-mediated VEGF | Negative feedback |
How Is positive regulation of vascular endothelial growth factor production Regulated?
Positive regulation of VEGF production is controlled by multiple signaling pathways. The PI3K/AKT/mTOR pathway enhances HIF-1α translation and stability, thereby increasing VEGF production. The unfolded protein response (UPR) and endoplasmic reticulum stress can also upregulate VEGF under pathological conditions. Inflammatory signaling through NF-κB and STAT3 integrates cytokine cues to fine-tune VEGF levels. Epigenetic modifiers such as histone lactyltransferases and demethylases (e.g., ALKBH3) add another layer of regulation, linking cellular metabolism to VEGF production. These regulatory nodes are potential therapeutic targets for diseases characterized by excessive angiogenesis.
positive regulation of vascular endothelial growth factor production and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| VEGFA | Cancer, psoriasis, AMD | Xenograft models, CRISPR KO in cancer cell lines |
| HIF1A | Hypoxia-driven angiogenesis | Hypoxia chamber studies, KO mice |
| MDK | Psoriasis | Skin inflammation models, overexpression in keratinocytes |
| ALKBH3 | Age-related macular degeneration | Retinal pigment epithelium cells, KO models |
| TGFB1 | Placental vascular dysfunction | Pericyte-specific KO, placental explants |
Cancer and Tumor Angiogenesis
In many solid tumors, positive regulation of VEGF production is hijacked to support neovascularization. scRNA-seq studies in non-small cell lung cancer revealed that VEGF signaling mediates the response to neoadjuvant anlotinib combined with PD-1 blockade therapy, highlighting the clinical relevance of VEGF production. Translocation renal cell carcinoma also exhibits dysregulated VEGF pathways, with integrative molecular characterization identifying VEGF as a key driver. Targeting positive regulators of VEGF production is therefore a rational anti-angiogenic strategy.
Inflammatory and Skin Diseases
Psoriasis is a chronic inflammatory skin disease characterized by excessive angiogenesis. Midkine has been shown to upregulate VEGFA in psoriasis, contributing to vascular hyperplasia and inflammation. Similarly, in endometriosis, hypoxia and inflammatory microenvironments stimulate VEGF production, promoting lesion vascularization and pain. These findings underscore the role of GO:0010575 in inflammatory pathologies.
Ocular Neovascular Diseases
Age-related macular degeneration (AMD) is a leading cause of blindness, driven in part by pathological VEGF production. Recent work has linked histone lactylation and ALKBH3-mediated glycolysis to feedback regulation of VEGF in AMD, revealing metabolic and epigenetic mechanisms that positively regulate VEGF production. This highlights GO:0010575 as a therapeutic target in ocular neovascularization.
Placental and Vascular Development
Proper regulation of VEGF production is essential for placental development. Placental pericytes regulate VEGF production through TGF-β1 signaling, influencing vascular function during pregnancy. Dysregulation of this process may contribute to pregnancy complications, though further research is needed.
From positive regulation of vascular endothelial growth factor production-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X causally increase VEGF production? | CRISPR knockout in relevant cell type |
| Does a specific point mutation in HIF1A affect VEGF induction? | Point-mutation knock-in via CRISPR |
| Can a reporter track VEGF production in real time? | Knock-in of fluorescent reporter at VEGFA locus |
| What is the effect of overexpressing midkine on VEGF? | Overexpression cell model |
| Which regulators are essential in tumor angiogenesis? | CRISPR library screening in cancer cells |
| How does TGF-β1 signaling in pericytes affect VEGF? | Pericyte-specific KO or knock-in |
How to Study the positive regulation of vascular endothelial growth factor production Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Transcriptome-wide mRNA levels | Identify regulators of VEGFA transcription |
| scRNA-seq | Single-cell gene expression | Dissect tumor heterogeneity in VEGF production |
| ELISA | Secreted VEGF protein | Quantify VEGF production in conditioned media |
| Western blot | Intracellular VEGF protein | Validate changes in VEGF levels |
| ChIP-seq | Transcription factor binding | Map HIF-1α or NF-κB binding to VEGFA promoter |
| MeRIP-seq | RNA methylation | Study ALKBH3-mediated VEGF regulation |
| CRISPR screen | Gene function at scale | Identify positive regulators of VEGF production |
Transcriptional Profiling
RNA-seq and scRNA-seq are powerful methods to identify genes and pathways that positively regulate VEGF production. For example, scRNA-seq revealed VEGF signaling as a mediator of therapy response in lung cancer. These approaches can quantify VEGFA mRNA and correlate it with candidate regulators.
Epigenetic and Metabolic Assays
Histone lactylation, DNA methylation, and RNA methylation can be assessed by ChIP-seq, bisulfite sequencing, and MeRIP-seq, respectively. Such methods have been used to link ALKBH3-mediated glycolysis to VEGF regulation in AMD. These techniques help uncover upstream regulatory layers of GO:0010575.
Protein-Level Quantification
ELISA, Western blot, and proteomics can measure VEGF protein levels in cell lysates and conditioned media. These are standard readouts for VEGF production and are used in studies of psoriasis, cancer, and placental biology.
Functional Genomics with CRISPR
CRISPR knockout, knock-in, and overexpression models enable causal testing of candidate regulators. For instance, CRISPR screens can identify genes whose loss reduces VEGF production in tumor cells. These models are essential for moving from correlation to causation.
How CRISPR Can Be Used to Study GO:0010575 positive regulation of vascular endothelial growth factor production
Knockout
CRISPR knockout of candidate genes such as HIF1A, NFKB1, or MDK can determine whether they are required for VEGF production. For example, knocking out HIF1A in hypoxic cancer cells reduces VEGFA transcription. Knockout models are essential for loss-of-function studies in GO:0010575 research.
Point Mutation
Point mutations can be introduced to mimic disease-associated variants or to disrupt specific phosphorylation sites in regulators. For instance, mutating the oxygen-dependent degradation domain of HIF1A can stabilize the protein and enhance VEGF production. Such models help dissect precise molecular mechanisms.
Knock-in
Knock-in of reporter genes (e.g., luciferase or fluorescent proteins) at the VEGFA locus allows real-time monitoring of VEGF production. This is valuable for high-throughput screening of positive regulators. Knock-in of tagged alleles also enables chromatin immunoprecipitation and proteomics.
Overexpression
Overexpression of candidate genes such as MDK or TGFB1 can test sufficiency in driving VEGF production. In psoriasis models, midkine overexpression increased VEGFA levels, supporting its role as a positive regulator. Overexpression models complement knockout studies to establish causality.
How EDITGENE Supports positive regulation of vascular endothelial growth factor production Research
Researchers studying positive regulation of vascular endothelial growth factor production-related genes often need to determine whether a candidate gene is causally involved in VEGF upregulation or merely correlated with it. EDITGENE provides a comprehensive suite of CRISPR-based services to accelerate this discovery process, from gene knockout to precise point mutations and library screening.
Contact EDITGENE today to design your custom CRISPR model for positive regulation of vascular endothelial growth factor production research.
Frequently Asked Questions About positive regulation of vascular endothelial growth factor production
What is GO:0010575?
GO:0010575 is the Gene Ontology term for positive regulation of vascular endothelial growth factor production, describing any process that increases the synthesis or release of VEGF.
What genes are involved in positive regulation of VEGF production?
Key genes include VEGFA, HIF1A, NFKB1, STAT3, MDK, TGFB1, and ALKBH3, among others.
How is VEGF production regulated?
VEGF production is regulated at transcriptional, post-transcriptional, and epigenetic levels by hypoxia, inflammatory cytokines, and metabolic signals.
What diseases are associated with increased VEGF production?
Cancer, psoriasis, endometriosis, age-related macular degeneration, and placental vascular disorders are linked to excessive VEGF production.
How can CRISPR be used to study VEGF production?
CRISPR knockout, knock-in, point mutation, and overexpression models allow causal testing of candidate regulators of VEGF production.
What is the role of HIF-1α in VEGF production?
HIF-1α is a transcription factor that activates VEGFA expression under hypoxia, making it a master positive regulator.
Is midkine a positive regulator of VEGF?
Yes, midkine upregulates VEGFA in psoriasis, acting as a positive regulator of VEGF production.
How does TGF-β1 affect VEGF production in the placenta?
TGF-β1 signaling in placental pericytes regulates VEGF production, influencing vascular function during pregnancy.
What methods measure VEGF production?
ELISA, Western blot, RNA-seq, and scRNA-seq are commonly used to measure VEGF production at protein and mRNA levels.
What is the link between ALKBH3 and VEGF in AMD?
ALKBH3-mediated glycolysis and histone lactylation form a feedback loop that regulates VEGF production in age-related macular degeneration.
Conclusion
GO:0010575, positive regulation of vascular endothelial growth factor production, is a critical biological process that integrates hypoxia, inflammation, and metabolic signals to control angiogenesis. Its dysregulation underlies major diseases including cancer, psoriasis, endometriosis, and AMD. CRISPR-based models and functional genomics are indispensable for dissecting the causal regulators of VEGF production and for developing targeted therapies.
References
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- 2. 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
- 3. Wang Y et al.. 2025. Feedback regulation between histone lactylation and ALKBH3-mediated glycolysis regulates age-related macular degeneration pathology.. Proc Natl Acad Sci U S A 122(24):e2416046122 PMID: 40493193
- 4. Li L et al.. 2023. Overexpression and potential roles of midkine via regulation of vascular endothelial growth factor A in psoriasis.. Exp Dermatol 32(9):1383-1393 PMID: 37218430
- 5. MacPhee CA et al.. 2025. The regulation of placental pericyte function through transforming growth factor β-1 signalling.. Sci Rep 15(1):36668 PMID: 41120412
- 6. Wilgus TA et al.. 2008. Regulation of scar formation by vascular endothelial growth factor.. Lab Invest 88(6):579-90 PMID: 18427552
- 7. Bakouny Z et al.. 2022. Integrative clinical and molecular characterization of translocation renal cell carcinoma.. Cell Rep 38(1):110190 PMID: 34986355
- 8. Yu W. 2025. Mechanism of vascular endothelial growth factor regulating hypoxia and inflammatory microenvironment in endometriosis: based on bioinformatics and multi-level validation.. Arch Biochem Biophys 774:110639 PMID: 41077175
