GO:0010574 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:0010574 describes any process that modulates the frequency, rate, or extent of production of vascular endothelial growth factor (VEGF).
• VEGF production is controlled at multiple levels, including transcription, mRNA stability, translation, and secretion, with hypoxia being a major inducer.
• Key regulators include HIF-1, VHL, growth factors, cytokines, and advanced glycation end products.
• Dysregulated VEGF production contributes to cancer, retinopathies, rheumatoid arthritis, and cardiovascular disease.
• Studying GO:0010574 requires models that capture dynamic changes in VEGF output, such as reporter cells, knockout models, and CRISPR screens.
• EDITGENE provides CRISPR services to dissect the regulatory network of VEGF production.
Description
Regulation of vascular endothelial growth factor (VEGF) production (GO:0010574) is a fundamental biological process that controls the amount of VEGF available to stimulate angiogenesis and vascular permeability. VEGF is a secreted mitogen that acts on endothelial cells to promote proliferation, migration, and survival, and its production is tightly regulated in both physiological and pathological settings. Understanding how VEGF production is modulated is critical for developing therapies that either enhance or inhibit angiogenesis. This article synthesizes current knowledge on the mechanisms, key genes, and research methods used to study GO:0010574, based on authoritative QuickGO data and published literature.
regulation of vascular endothelial growth factor production At A Glance
| GO ID | GO:0010574 |
|---|---|
| GO term | regulation of vascular endothelial growth factor production |
| Ontology | biological_process |
| Synonym | None |
| Major function | Modulates the synthesis and secretion of VEGF |
| Key regulators | HIF-1, VHL, growth factors, cytokines, AGEs |
| Associated diseases | Cancer, retinopathy, rheumatoid arthritis, cardiovascular disease |
| Research methods | Reporter assays, CRISPR screens, RNA-seq, proteomics |
What Is GO:0010574?
GO:0010574, regulation of vascular endothelial growth factor production, refers to any process that modulates the frequency, rate, or extent of the production of vascular endothelial growth factor (VEGF). This includes transcriptional, post-transcriptional, translational, and secretory control mechanisms that determine the amount of VEGF protein released by a cell.
Why Is regulation of vascular endothelial growth factor production Important in Cell Biology?
VEGF is a master regulator of angiogenesis and vascular permeability, and its production must be precisely controlled to maintain tissue homeostasis. Dysregulated VEGF production is a hallmark of many diseases, including cancer, where it drives tumor angiogenesis, and ocular disorders, where it causes macular edema. Therefore, understanding the regulation of VEGF production is essential for identifying therapeutic targets and developing strategies to modulate angiogenesis.
• Controls angiogenesis during development and tissue repair.
• Mediates vascular permeability in inflammation and edema.
• Promotes tumor growth and metastasis by supporting tumor vasculature.
• Involved in the pathogenesis of diabetic retinopathy and age-related macular degeneration.
• Plays a role in rheumatoid arthritis by enhancing synovial angiogenesis.
• Regulated by hypoxia via HIF-1 and VHL, linking metabolism to angiogenesis.
• Modulated by advanced glycation end products in diabetes.
• Essential for ovarian follicle angiogenesis and growth.
• Affects viability and steroidogenesis in granulosa cells.
• Target for anti-angiogenic therapies in cancer and ophthalmology.
What Happens During regulation of vascular endothelial growth factor production?
Transcriptional control of VEGF
In simple terms: The cell decides how much VEGF mRNA to make.
VEGF production is primarily regulated at the transcriptional level. Hypoxia-inducible factor 1 (HIF-1) binds to hypoxia response elements in the VEGF promoter and enhances transcription under low oxygen conditions. The von Hippel-Lindau tumor suppressor gene product (pVHL) targets HIF-1 for degradation under normoxia, thereby suppressing VEGF production. Growth factors and cytokines can also activate transcription factors such as Sp1 and AP-1 to increase VEGF mRNA levels.
Post-transcriptional regulation of VEGF mRNA
In simple terms: The cell controls how long VEGF mRNA survives and how efficiently it is translated.
VEGF mRNA stability and translation are modulated by RNA-binding proteins and microRNAs. For example, hypoxia can stabilize VEGF mRNA through the binding of proteins to the 3' untranslated region. Additionally, advanced glycation end products (AGEs) have been shown to increase VEGF expression by enhancing mRNA stability and translation in certain cell types.
Translational control of VEGF
In simple terms: The cell adjusts how much VEGF protein is made from each mRNA.
Translational regulation allows rapid changes in VEGF protein levels without new transcription. The 5' untranslated region of VEGF mRNA contains an internal ribosome entry site (IRES) that permits cap-independent translation under stress conditions. This mechanism ensures VEGF production even when global translation is inhibited, such as during hypoxia.
Secretion and extracellular modulation
In simple terms: VEGF is released from the cell and can be further activated or stored.
VEGF is secreted as a homodimer that can bind to heparan sulfate proteoglycans in the extracellular matrix, creating a reservoir of growth factor. Proteases can release matrix-bound VEGF, thereby regulating its bioavailability. This extracellular modulation is a key aspect of VEGF production regulation, as it determines the amount of active VEGF available to endothelial cells.
Key Genes Involved in GO:0010574 regulation of vascular endothelial growth factor production
The following genes and proteins are central to the regulation of VEGF production, as supported by published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| VEGFA | Encodes VEGF-A, the major angiogenic factor | Target for anti-angiogenic therapy; knockout models |
| HIF1A | Transcription factor induced by hypoxia; activates VEGF transcription | Knockout reduces VEGF production; drug target |
| VHL | Targets HIF-1 for degradation; suppresses VEGF production | Tumor suppressor; mutations cause von Hippel-Lindau disease |
| EPAS1 | Encodes HIF-2α; regulates VEGF under hypoxia | Polymorphisms associated with adaptation; knockout models |
| SP1 | Transcription factor that binds VEGF promoter | Modulates basal VEGF expression; knockdown studies |
| STAT3 | Transcription factor activated by cytokines; induces VEGF | Involved in inflammation-driven angiogenesis |
| NFKB1 | Transcription factor that promotes VEGF expression | Links inflammation to angiogenesis |
| EGR1 | Early growth response protein 1; regulates VEGF transcription | Knockout impairs VEGF induction |
| AGER | Receptor for advanced glycation end products; induces VEGF | Mediates diabetic complications |
| TGFB1 | Cytokine that induces VEGF production | Knockout affects vascular development |
| IL6 | Cytokine that stimulates VEGF via STAT3 | Involved in rheumatoid arthritis |
| TNF | Cytokine that upregulates VEGF | Inflammation-associated angiogenesis |
| IGF1 | Growth factor that enhances VEGF expression | Knockout models show reduced angiogenesis |
| NOS3 | Endothelial nitric oxide synthase; modulates VEGF signaling | Knockout affects vascular permeability |
| PTGS2 | Cyclooxygenase-2; prostaglandins induce VEGF | Inhibitors reduce VEGF production |
| MMP9 | Matrix metalloproteinase-9; releases matrix-bound VEGF | Knockout impairs angiogenesis |
| PLG | Plasminogen; generates plasmin that releases VEGF | Knockout models show defective wound healing |
| NRP1 | Neuropilin-1; co-receptor for VEGF | Modulates VEGF signaling; knockout embryonic lethal |
How Is regulation of vascular endothelial growth factor production Regulated?
VEGF production is regulated by multiple signaling pathways. The PI3K/AKT/mTOR pathway enhances VEGF translation and stability. Hypoxia signaling via HIF-1 is a major regulator, with prolyl hydroxylases (PHDs) and VHL controlling HIF-1 stability. Inflammatory cytokines such as IL-6 and TNF activate STAT3 and NF-κB, leading to increased VEGF transcription. Advanced glycation end products, formed in diabetes, can also upregulate VEGF production through their receptor AGER. Additionally, microRNAs and RNA-binding proteins fine-tune VEGF mRNA stability and translation.
regulation of vascular endothelial growth factor production and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| VEGFA | Cancer, retinopathy | Knockout mice, xenograft models |
| HIF1A | Cancer, ischemia | Conditional knockout, hypoxia models |
| VHL | Von Hippel-Lindau disease | Knockout cell lines, zebrafish |
| AGER | Diabetic complications | Knockout mice, AGE-treated cells |
| IL6 | Rheumatoid arthritis | Knockout mice, synovial fibroblasts |
VEGF production in cancer
Many tumors overproduce VEGF, which promotes angiogenesis and supports tumor growth and metastasis. Hypoxia within the tumor microenvironment induces HIF-1, leading to increased VEGF transcription. Oncogenic mutations in RAS, EGFR, and other pathways can also enhance VEGF production. Anti-VEGF therapies, such as bevacizumab, are used to inhibit tumor angiogenesis.
VEGF production in ocular diseases
Diabetic retinopathy and age-related macular degeneration are characterized by excessive VEGF production, leading to vascular leakage and neovascularization. Hypoxia and advanced glycation end products contribute to VEGF upregulation in these conditions. Anti-VEGF agents are standard treatments for these diseases.
VEGF production in inflammatory arthritis
In rheumatoid arthritis, pro-inflammatory cytokines such as TNF and IL-6 stimulate VEGF production in synovial fibroblasts, promoting angiogenesis and pannus formation. Cyclosporine has been shown to inhibit VEGF production in these cells. Targeting VEGF production may reduce joint damage.
VEGF production in reproductive biology
VEGF is essential for ovarian follicle angiogenesis and growth. In yak granulosa cells, VEGF affects viability, apoptosis, and steroidogenesis. Dysregulated VEGF production may contribute to ovarian dysfunction.
From regulation of vascular endothelial growth factor production-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X regulate VEGF production? | CRISPR knockout in cell lines (e.g., HeLa, HEK293) |
| Does mutation Y affect VEGF secretion? | Point mutation knock-in in VEGF reporter cells |
| Can we tag endogenous VEGF for live imaging? | Knock-in of fluorescent tag at VEGFA locus |
| Does overexpression of gene Z increase VEGF? | Doxycycline-inducible overexpression in endothelial cells |
| Which genes are essential for VEGF production? | Genome-wide CRISPR library screening |
| How does hypoxia affect VEGF production? | HIF-1 knockout cells under hypoxia |
How to Study the regulation of vascular endothelial growth factor production Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Luciferase reporter assay | VEGF promoter activity | Screening for transcriptional regulators |
| RNA-seq | VEGF mRNA levels and variants | Transcriptomic profiling |
| ELISA | Secreted VEGF protein | Quantifying production in conditioned media |
| Western blot | Intracellular VEGF protein | Validating knockdown/knockout effects |
| CRISPR knockout screen | Genes affecting VEGF production | Identifying novel regulators |
| CRISPR activation screen | Genes whose overexpression increases VEGF | Discovering enhancers |
| Proteomics | VEGF-interacting proteins | Mapping regulatory complexes |
| Imaging | VEGF secretion dynamics | Live-cell imaging with tagged VEGF |
Reporter assays for VEGF production
VEGF promoter or 3'UTR luciferase reporters are used to measure transcriptional and post-transcriptional regulation. These assays can be scaled for high-throughput screening.
RNA sequencing and transcriptomics
RNA-seq quantifies VEGF mRNA levels and identifies splicing variants or stability changes. It can also reveal co-regulated genes in the VEGF pathway.
Proteomics and ELISA
VEGF protein levels in cell lysates or conditioned media are measured by ELISA or Western blot. Mass spectrometry can detect post-translational modifications.
CRISPR screens
Genome-wide CRISPR knockout or activation screens identify genes that regulate VEGF production. These screens use VEGF-dependent reporter cells or survival assays.
How CRISPR Can Be Used to Study GO:0010574 regulation of vascular endothelial growth factor production
Knockout
CRISPR knockout of candidate genes (e.g., HIF1A, VHL) is used to determine their role in VEGF production. Knockout cell lines can be generated in various backgrounds and validated by sequencing and functional assays.
Point Mutation
Point mutations can be introduced to mimic disease-associated variants or to disrupt specific regulatory sites in the VEGF promoter or 3'UTR. These models help dissect the precise mechanisms of VEGF regulation.
Knock-in
Knock-in of reporter genes (e.g., luciferase, GFP) at the endogenous VEGFA locus allows real-time monitoring of VEGF production. Tagged knock-in models also enable studies of VEGF trafficking and secretion.
Overexpression
CRISPR activation (CRISPRa) or cDNA overexpression can be used to study the effects of increased gene dosage on VEGF production. Overexpression models are valuable for identifying sufficiency of a regulator.
How EDITGENE Supports regulation of vascular endothelial growth factor production Research
Researchers studying regulation of vascular endothelial growth factor production-related genes often need to determine whether a candidate gene is causally involved in VEGF regulation. EDITGENE provides comprehensive CRISPR services to generate precisely engineered cell models, enabling functional validation and mechanistic studies.
Contact EDITGENE today to design your custom CRISPR model for regulation of vascular endothelial growth factor production research.
Frequently Asked Questions About regulation of vascular endothelial growth factor production
What is GO:0010574?
GO:0010574 is the Gene Ontology term for regulation of vascular endothelial growth factor production, describing any process that modulates the frequency, rate, or extent of VEGF production.
What genes are involved in regulation of VEGF production?
Key genes include VEGFA, HIF1A, VHL, EPAS1, SP1, STAT3, NFKB1, and AGER, among others.
How is VEGF production regulated by hypoxia?
Hypoxia stabilizes HIF-1, which binds to hypoxia response elements in the VEGF promoter and increases transcription.
What diseases are associated with dysregulated VEGF production?
Cancer, diabetic retinopathy, age-related macular degeneration, rheumatoid arthritis, and cardiovascular diseases.
What methods are used to study VEGF production?
Reporter assays, RNA-seq, ELISA, Western blot, CRISPR screens, and proteomics.
Can CRISPR be used to study VEGF production?
Yes, CRISPR knockout, knock-in, point mutation, and overexpression models are widely used to dissect VEGF regulatory mechanisms.
What is the role of VHL in VEGF production?
VHL targets HIF-1 for degradation, thereby suppressing VEGF production under normoxic conditions.
How do advanced glycation end products affect VEGF production?
AGEs can increase VEGF expression through their receptor AGER, contributing to diabetic complications.
What is the relationship between VEGF and ovarian function?
VEGF regulates ovarian follicle angiogenesis and growth, and affects granulosa cell viability and steroidogenesis.
How can I model VEGF production regulation in the lab?
Use CRISPR-engineered cell lines with reporters, knockouts, or overexpression, combined with functional assays.
Conclusion
Regulation of VEGF production (GO:0010574) is a critical biological process with profound implications for angiogenesis, vascular permeability, and disease. Understanding its mechanisms through CRISPR-based models and other advanced techniques can reveal new therapeutic targets. EDITGENE offers a suite of services to facilitate this research, from knockout to library screening.
References
- 1. Zachary I. 1998. Vascular endothelial growth factor.. Int J Biochem Cell Biol 30(11):1169-74 PMID: 9839443
- 2. Levy AP et al.. 1997. Regulation of vascular endothelial growth factor by hypoxia and its modulation by the von Hippel-Lindau tumor suppressor gene.. Kidney Int 51(2):575-8 PMID: 9027742
- 3. Bates DO et al.. 2002. Regulation of microvascular permeability by vascular endothelial growth factors.. J Anat 200(6):581-97 PMID: 12162726
- 4. Treins C et al.. 2001. Regulation of vascular endothelial growth factor expression by advanced glycation end products.. J Biol Chem 276(47):43836-41 PMID: 11571295
- 5. Guzmán A et al.. 2023. The vascular endothelial growth factor (VEGF) system as a key regulator of ovarian follicle angiogenesis and growth.. Mol Reprod Dev 90(4):201-217 PMID: 36966489
- 6. Cho ML et al.. 2002. Cyclosporine inhibition of vascular endothelial growth factor production in rheumatoid synovial fibroblasts.. Arthritis Rheum 46(5):1202-9 PMID: 12115224
- 7. Neufeld G et al.. 1999. Vascular endothelial growth factor (VEGF) and its receptors.. FASEB J 13(1):9-22 PMID: 9872925
- 8. Wu JF et al.. 2023. Effects of vascular endothelial growth factor (VEGF) on the viability, apoptosis and steroidogenesis of yak (Bos grunniens) granulosa cells.. Theriogenology 207:1-10 PMID: 37245256
