GO:1900746 regulation of vascular endothelial growth factor signaling pathway: Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1900746 describes any process that modulates the frequency, rate or extent of vascular endothelial growth factor (VEGF) signaling, a central pathway controlling angiogenesis and vascular permeability.
• VEGF ligands (VEGFA, VEGFB, VEGFC, VEGFD, PlGF) bind VEGFR1/2/3 and co-receptors such as NRP1/2 to activate downstream cascades including PLCγ-PKC, PI3K-AKT and RAS-MAPK.
• Regulation occurs at multiple levels: ligand expression (hypoxia, estrogens, progestins), receptor trafficking and co-receptor availability, microRNA control, and feedback phosphatases.
• Dysregulated VEGF signaling underlies tumor angiogenesis, corneal avascularity defects, liver regeneration impairment, and retinopathies.
• CRISPR knockout, point-mutation, knock-in and overexpression models enable causal dissection of VEGF pathway regulators in endothelial and non-endothelial cells.
• Functional readouts include tube formation, sprouting assays, phospho-VEGFR2 immunoblotting, and transcriptomic or proteomic profiling of angiogenic programs.
Description
The Gene Ontology term GO:1900746, regulation of vascular endothelial growth factor signaling pathway, refers to any process that modulates the frequency, rate or extent of the signaling cascade initiated by VEGF family ligands. VEGF signaling is one of the most intensely studied pathways in vascular biology because it governs endothelial cell proliferation, migration, survival and permeability, and because its dysregulation is a hallmark of numerous pathological conditions. Since the original identification of VEGF as a vascular permeability factor and its receptors, research has expanded from ligand-receptor biochemistry to a sophisticated understanding of how this pathway is tuned by co-receptors, intracellular trafficking, phosphatases, microRNAs and hormonal cues. Understanding the regulation of VEGF signaling is therefore essential for both developmental biology and translational medicine, as it directly informs anti-angiogenic therapies and tissue regeneration strategies. This article synthesizes authoritative QuickGO annotation and verified PubMed literature to provide a research-grade overview of GO:1900746, its molecular players, disease relevance and experimental approaches.
regulation of vascular endothelial growth factor signaling pathway At A Glance
| GO ID | GO:1900746 |
|---|---|
| GO term | regulation of vascular endothelial growth factor signaling pathway |
| Ontology | biological_process |
| Synonym | regulation of VEGF signaling; regulation of VEGF-activated signaling pathway; regulation of vascular endothelial growth factor signalling pathway |
| Major function | Modulates the frequency, rate or extent of VEGF signaling, thereby controlling angiogenesis, vascular permeability and endothelial cell behavior |
| Key ligands | VEGFA, VEGFB, VEGFC, VEGFD, PlGF |
| Key receptors | VEGFR1 (FLT1), VEGFR2 (KDR), VEGFR3 (FLT4), NRP1, NRP2 |
| Downstream modules | PLCγ-PKC, PI3K-AKT, RAS-MAPK, SRC-FAK |
| Regulatory layers | Transcriptional (hypoxia, hormones), post-transcriptional (miRNAs), receptor trafficking, phosphatases |
What Is GO:1900746?
GO:1900746 is a biological process term defined as any process that modulates the frequency, rate or extent of the vascular endothelial growth factor signaling pathway. In other words, it encompasses all molecular events that positively or negatively adjust the intensity, duration or spatial distribution of VEGF-triggered signals, from ligand availability and receptor activation to downstream second messenger and transcriptional outputs.
Why Is regulation of vascular endothelial growth factor signaling pathway Important in Cell Biology?
Regulation of VEGF signaling is critically important because it determines whether blood vessels grow, remain quiescent or become leaky, and because its perturbation contributes to cancer, ischemic disease, retinopathies and impaired tissue regeneration. The pathway is also a prime therapeutic target: anti-VEGF agents are used clinically, yet resistance and side effects highlight the need to understand endogenous regulatory mechanisms. Moreover, VEGF signaling intersects with hormonal regulation, microRNA networks and organ-specific regeneration programs, making GO:1900746 a hub for interdisciplinary research.
• Controls developmental and pathological angiogenesis, including tumor vascularization.
• Regulates vascular permeability and endothelial barrier function.
• Modulated by steroid hormones such as estrogens and progestins in reproductive tissues.
• Fine-tuned by microRNAs during vascular development.
• Required for liver regeneration through effects on liver sinusoidal endothelial cells.
• Dysregulation linked to corneal avascularity defects and neovascular eye diseases.
• Provides targets for anti-angiogenic therapy and vascular normalization strategies.
• Serves as a paradigm for receptor tyrosine kinase signaling regulation.
• Involved in organ-specific endothelial heterogeneity and regeneration.
• Offers a rich source of candidate genes for CRISPR functional screens.
What Happens During regulation of vascular endothelial growth factor signaling pathway?
Ligand availability and receptor binding
In simple terms: The amount of VEGF ligand and the presence of its receptors determine how strongly the signal starts.
VEGF family ligands (VEGFA, VEGFB, VEGFC, VEGFD, PlGF) are secreted glycoproteins whose expression is controlled by hypoxia, growth factors and hormones. They bind with distinct affinities to VEGFR1, VEGFR2 and VEGFR3, and to co-receptors NRP1/2, which modulate ligand presentation and receptor selectivity. Regulation at this step includes transcriptional induction of VEGFA by HIF-1α under low oxygen, hormonal upregulation by estrogens and progestins, and sequestration by soluble decoy receptors such as sVEGFR1.
Receptor activation and intracellular trafficking
In simple terms: Once VEGF binds, the receptor switches on and moves inside the cell, where its signal can be amplified or shut down.
Ligand binding induces VEGFR2 dimerization, autophosphorylation and activation of downstream effectors. Receptor endocytosis, recycling and degradation are actively regulated processes that determine signal duration and specificity. Neuropilin co-receptors and integrins influence receptor internalization and signaling output, while phosphatases such as VE-PTP and PTP1B dephosphorylate VEGFR2 to terminate signaling.
Downstream signaling cascades
In simple terms: Activated receptors turn on several molecular switches that tell endothelial cells to grow, move and survive.
Phosphorylated VEGFR2 recruits PLCγ, which generates IP3 and DAG to activate PKC and calcium signaling; it also activates PI3K-AKT for survival and RAS-MAPK for proliferation. SRC-family kinases and FAK regulate cytoskeletal reorganization and migration. These cascades are modulated by scaffold proteins, adaptors and negative feedback loops, including Sprouty and DUSP phosphatases.
MicroRNA and post-transcriptional control
In simple terms: Small RNA molecules can dial down the production of VEGF pathway components.
MicroRNAs such as miR-126, miR-200b and others target VEGF ligands, receptors or downstream effectors, thereby shaping vascular development and pathological angiogenesis. These microRNAs provide a reversible, fine-tuned layer of regulation that can be exploited experimentally to modulate VEGF signaling output.
Integration with organ-specific and hormonal cues
In simple terms: Different tissues and hormones adjust VEGF signaling to fit their needs.
In the liver, VEGF signaling regulates liver sinusoidal endothelial cells during regeneration after partial hepatectomy, illustrating organ-specific regulatory mechanisms. In reproductive tissues, estrogens and progestins regulate VEGF expression, linking hormonal status to angiogenic potential. In the cornea, FoxC1-dependent regulation maintains avascularity by modulating VEGF signaling.
Key Genes Involved in GO:1900746 regulation of vascular endothelial growth factor signaling pathway
The following genes and proteins are central to the regulation of VEGF signaling and are frequently studied using CRISPR-based approaches.
| Gene | Major Role | Research Relevance |
|---|---|---|
| VEGFA | Primary angiogenic ligand; binds VEGFR2 | Target for anti-angiogenic therapy; knockout models show vascular defects |
| VEGFB | Ligand for VEGFR1; involved in lipid transport and survival | Less pro-angiogenic; studied for metabolic roles |
| VEGFC | Ligand for VEGFR3; lymphangiogenesis | Knockout causes lymphatic defects |
| VEGFD | Ligand for VEGFR3; lymphatic and vascular roles | Investigated in lymphangiogenesis and cancer |
| PGF (PlGF) | VEGFR1 ligand; modulates angiogenesis | Studied in tumor angiogenesis and inflammation |
| FLT1 (VEGFR1) | Receptor; decoy and signaling modulator | Soluble form regulates ligand availability |
| KDR (VEGFR2) | Main signaling receptor for VEGFA | Central to endothelial proliferation and migration |
| FLT4 (VEGFR3) | Receptor for VEGFC/D; lymphangiogenesis | Target in lymphatic disorders |
| NRP1 | Co-receptor enhancing VEGFR2 signaling | Modulates ligand binding and receptor trafficking |
| NRP2 | Co-receptor for VEGFC/D and semaphorins | Involved in lymphatic and neural guidance |
| FOXC1 | Transcription factor regulating VEGF signaling in cornea | Maintains corneal avascularity |
| HIF1A | Hypoxia-inducible factor; induces VEGFA | Master regulator of hypoxic VEGF expression |
| ESR1 | Estrogen receptor; regulates VEGF expression | Links hormonal status to angiogenesis |
| PGR | Progesterone receptor; modulates VEGF | Reproductive tissue angiogenesis |
| MIR126 | MicroRNA targeting VEGF pathway components | Regulates vascular development |
| MIR200B | MicroRNA modulating VEGF signaling | Influences angiogenesis and tumor growth |
| PTPRB (VE-PTP) | Phosphatase dephosphorylating VEGFR2 | Negative regulator of VEGF signaling |
How Is regulation of vascular endothelial growth factor signaling pathway Regulated?
Regulation of VEGF signaling is itself regulated at multiple levels. Transcriptionally, HIF-1α induces VEGFA under hypoxia, while estrogen and progesterone receptors modulate VEGF expression in reproductive tissues. Post-transcriptionally, microRNAs such as miR-126 and miR-200b fine-tune pathway component levels. At the protein level, receptor trafficking, ubiquitination and dephosphorylation by phosphatases like VE-PTP control signal duration. Additionally, soluble decoy receptors (sVEGFR1) and co-receptors (NRP1/2) adjust ligand availability and receptor selectivity. Organ-specific cues, such as FoxC1 in the cornea and VEGF signaling in liver regeneration, further illustrate context-dependent regulation.
regulation of vascular endothelial growth factor signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| VEGFA | Tumor angiogenesis; retinopathies | Knockout or overexpression in endothelial cells; xenograft models |
| KDR (VEGFR2) | Angiogenesis-dependent cancers | Point mutation of phosphorylation sites; knock-in reporter |
| FOXC1 | Corneal avascularity defects | Knockout in corneal epithelial cells |
| HIF1A | Hypoxia-driven angiogenesis in cancer | Knockout under hypoxia; overexpression |
| MIR126 | Vascular development defects | Knockout and overexpression in zebrafish or mice |
Cancer and tumor angiogenesis
VEGF signaling is a hallmark of tumor angiogenesis, and its dysregulation promotes tumor growth and metastasis. Anti-VEGF therapies are used clinically, but resistance mechanisms often involve alternative pro-angiogenic pathways or increased expression of VEGF pathway components. Understanding the regulatory layers of GO:1900746 can reveal new targets for combination therapies.
Ocular neovascularization and corneal avascularity
In the cornea, FoxC1-dependent regulation of VEGF signaling maintains avascularity, and its disruption leads to neovascularization. In retinopathies such as diabetic retinopathy and age-related macular degeneration, excessive VEGF signaling causes pathological vessel growth and leakage. Modulating regulatory nodes could offer therapeutic opportunities.
Liver regeneration and sinusoidal endothelial cells
VEGF signaling regulates liver sinusoidal endothelial cells during liver regeneration after partial hepatectomy, and impaired regulation may contribute to regeneration failure. This highlights the importance of organ-specific VEGF regulatory mechanisms in regenerative medicine.
Reproductive and hormonal disorders
Estrogens and progestins regulate VEGF expression, linking hormonal signaling to angiogenesis in reproductive tissues. Dysregulation may contribute to conditions such as endometriosis and reproductive cancers, where VEGF signaling is often aberrant.
From regulation of vascular endothelial growth factor signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does a candidate gene regulate VEGF signaling? | CRISPR knockout in endothelial cells followed by phospho-VEGFR2 and tube formation assays |
| Which phosphorylation site on VEGFR2 mediates a specific output? | Point mutation knock-in of VEGFR2 phospho-null or phospho-mimetic |
| How does a regulatory protein localize during VEGF stimulation? | Tagged knock-in (e.g., GFP) of the endogenous gene |
| Does overexpression of a microRNA alter VEGF signaling? | Stable overexpression of miR-126 or miR-200b in endothelial cells |
| What is the role of FoxC1 in corneal avascularity? | Tissue-specific knockout in mouse cornea |
| How does VEGF signaling affect liver regeneration? | Liver-specific knockout or overexpression in partial hepatectomy models |
How to Study the regulation of vascular endothelial growth factor signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Phospho-VEGFR2 immunoblot | Receptor activation status | Validation of regulatory genes |
| RNA-seq | Transcriptional changes in VEGF pathway | Identifying feedback and crosstalk |
| Small RNA-seq | MicroRNA expression | Discovering miRNA regulators |
| Tube formation assay | Endothelial morphogenesis | Functional output of VEGF signaling |
| Spheroid sprouting assay | Angiogenic sprouting | Testing pro- or anti-angiogenic regulators |
| CRISPR knockout screen | Gene requirement for VEGF signaling | Unbiased discovery of regulators |
| Live imaging in zebrafish | Vascular development in vivo | Studying microRNA control |
| Liver regeneration model | Hepatocyte proliferation and LSEC function | Organ-specific VEGF regulation |
Phospho-proteomics and immunoblotting
Measuring phosphorylation of VEGFR2 and downstream effectors (PLCγ, AKT, ERK) by immunoblotting or mass spectrometry provides a direct readout of VEGF signaling activity. These methods are essential for validating regulatory mechanisms identified by genetic screens.
Transcriptomic and microRNA profiling
RNA-seq and small RNA-seq can reveal changes in VEGF pathway gene expression and microRNA networks upon perturbation. This is particularly useful for identifying feedback loops and compensatory mechanisms.
Functional angiogenesis assays
Tube formation, spheroid sprouting, and aortic ring assays measure the functional output of VEGF signaling in endothelial cells. These are often combined with CRISPR knockout to test causality.
In vivo models and imaging
Zebrafish, mouse retinal models and tumor xenografts allow real-time imaging of vascular development and permeability. Genetic manipulation via CRISPR enables tissue-specific analysis of regulatory genes.
How CRISPR Can Be Used to Study GO:1900746 regulation of vascular endothelial growth factor signaling pathway
Knockout
CRISPR knockout of candidate regulatory genes (e.g., VEGFA, KDR, FOXC1, MIR126) in endothelial or organ-specific cells allows assessment of their requirement for VEGF signaling. Readouts include phospho-VEGFR2 levels, tube formation and in vivo vascular phenotypes.
Point Mutation
Introducing point mutations into VEGFR2 phosphorylation sites or into regulatory proteins can dissect specific signaling outputs. For example, phospho-null or phospho-mimetic mutations clarify the role of individual tyrosines in downstream activation.
Knock-in
Knock-in of fluorescent tags (e.g., GFP) or epitope tags into endogenous loci enables real-time tracking of protein localization and interaction during VEGF stimulation. This is valuable for studying receptor trafficking and co-receptor dynamics.
Overexpression
CRISPR activation or cDNA overexpression of VEGF pathway components (e.g., VEGFA, miR-126) can model gain-of-function states observed in cancer and retinopathies. Overexpression models help identify sufficiency of a regulator to drive angiogenesis.
How EDITGENE Supports regulation of vascular endothelial growth factor signaling pathway Research
Researchers studying regulation of vascular endothelial growth factor signaling pathway-related genes often need to determine whether a candidate gene is causally involved in modulating VEGF signaling, and to dissect the precise molecular mechanism. EDITGENE provides end-to-end CRISPR services to generate precisely engineered cell models that answer these questions.
Contact EDITGENE today to design your custom CRISPR model for regulation of vascular endothelial growth factor signaling pathway research.
Frequently Asked Questions About regulation of vascular endothelial growth factor signaling pathway
What is GO:1900746?
GO:1900746 is the Gene Ontology term for regulation of vascular endothelial growth factor signaling pathway, describing any process that modulates the frequency, rate or extent of VEGF signaling.
What genes are involved in regulation of VEGF signaling?
Key genes include VEGFA, VEGFB, VEGFC, VEGFD, PGF, FLT1, KDR, FLT4, NRP1, NRP2, FOXC1, HIF1A, ESR1, PGR, MIR126 and MIR200B.
How is VEGF signaling regulated?
It is regulated at multiple levels: ligand expression (hypoxia, hormones), receptor trafficking and co-receptors, microRNAs, and phosphatases such as VE-PTP.
What diseases are associated with dysregulated VEGF signaling?
Cancer, ocular neovascularization, corneal avascularity defects, liver regeneration failure and reproductive disorders.
What experimental models are used to study VEGF signaling regulation?
CRISPR knockout, point mutation, knock-in and overexpression in endothelial cells, zebrafish, and mouse models of angiogenesis and regeneration.
How does FoxC1 regulate VEGF signaling?
FoxC1-dependent regulation maintains corneal avascularity by modulating VEGF signaling, and its disruption leads to neovascularization.
What is the role of microRNAs in VEGF signaling?
MicroRNAs such as miR-126 and miR-200b control VEGF signaling output during vascular development by targeting pathway components.
How do estrogens regulate VEGF expression?
Estrogens and progestins regulate VEGF expression in reproductive tissues, linking hormonal status to angiogenesis.
What is the role of VEGF signaling in liver regeneration?
VEGF signaling regulates liver sinusoidal endothelial cells during liver regeneration after partial hepatectomy.
How can CRISPR help study regulation of VEGF signaling?
CRISPR knockout, point mutation, knock-in and overexpression enable causal dissection of regulatory genes and their mechanisms in VEGF signaling.
Conclusion
GO:1900746, regulation of vascular endothelial growth factor signaling pathway, is a central biological process that integrates ligand availability, receptor activation, downstream cascades and post-transcriptional control to shape angiogenesis and vascular function. Its dysregulation is implicated in cancer, ocular diseases, liver regeneration and hormonal disorders, making it a prime target for both basic and translational research. CRISPR-based models offer powerful tools to dissect these regulatory mechanisms with precision, and EDITGENE provides comprehensive services to support such studies.
References
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- 7. Lu J et al.. 2021. The vascular endothelial growth factor signaling pathway regulates liver sinusoidal endothelial cells during liver regeneration after partial hepatectomy.. Expert Rev Gastroenterol Hepatol 15(2):139-147 PMID: 32902336
- 8. Dang LT et al.. 2013. MicroRNA control of vascular endothelial growth factor signaling output during vascular development.. Arterioscler Thromb Vasc Biol 33(2):193-200 PMID: 23325476
