GO:0035924 cellular response to vascular endothelial growth factor stimulus: Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0035924 describes all cellular changes triggered by vascular endothelial growth factor (VEGF) stimulation, including movement, secretion, enzyme production, and gene expression.
• VEGF signaling is essential for angiogenesis, vascular permeability, and endothelial cell survival, and is implicated in cancer, cardiovascular disease, and tissue repair.
• Key genes include VEGFA, KDR (VEGFR2), FLT1 (VEGFR1), and NRP1, which coordinate downstream pathways such as MAPK/ERK and PI3K/AKT.
• The response is regulated by oxygen tension, shear stress, and feedback loops involving VEGFR1 and neuropilins.
• Dysregulated VEGF signaling contributes to tumor angiogenesis, diabetic retinopathy, and inflammatory diseases.
• CRISPR-based models (knockout, knock-in, overexpression) enable precise dissection of VEGF-driven cellular responses in endothelial and non-endothelial cells.
Description
The Gene Ontology term GO:0035924, cellular response to vascular endothelial growth factor stimulus, defines the set of cellular processes that are initiated when a cell encounters vascular endothelial growth factor (VEGF). This includes changes in cell movement, secretion, enzyme activity, and gene expression that collectively mediate angiogenesis, vascular permeability, and cell survival. VEGF is a critical regulator of both physiological and pathological blood vessel formation, and its signaling is tightly controlled in space and time. Understanding this response is fundamental for researchers studying vascular biology, cancer, and regenerative medicine. The term encompasses responses to all VEGF family members, including VEGFA and VEGFB, and is observed in endothelial cells as well as other cell types such as osteoblasts and dental pulp cells. Because VEGF signaling is often hijacked in disease, it represents a major therapeutic target and a rich area for functional genomics.
cellular response to vascular endothelial growth factor stimulus At A Glance
| GO ID | GO:0035924 |
|---|---|
| GO term | cellular response to vascular endothelial growth factor stimulus |
| Ontology | biological_process |
| Synonym | cellular response to VEGF; cellular response to VEGFA; cellular response to VEGFB |
| Major function | Mediates cellular changes induced by VEGF, including angiogenesis, permeability, and survival |
| Related cellular component | Plasma membrane, endosomes, and extracellular matrix |
| Related molecular function | VEGF receptor binding and tyrosine kinase activity |
| Taxonomic range | Metazoa, primarily vertebrates |
What Is GO:0035924?
GO:0035924 is defined as any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a vascular endothelial growth factor stimulus. In simpler terms, it is the entire set of cellular reactions triggered by VEGF, from immediate signaling events to long-term changes in gene expression and behavior.
Why Is cellular response to vascular endothelial growth factor stimulus Important in Cell Biology?
VEGF signaling is a cornerstone of vascular biology and is essential for embryonic development, wound healing, and tissue homeostasis. Its dysregulation is a hallmark of numerous diseases, including cancer, where it drives tumor angiogenesis and metastasis, and ocular disorders such as diabetic retinopathy. Moreover, VEGF responses are critical for bone formation and dental pulp biology, highlighting its broad physiological relevance. Studying GO:0035924 therefore provides insights into both normal physiology and disease mechanisms, and informs the development of anti-angiogenic therapies.
• Essential for angiogenesis and vascular remodeling in development and repair.
• Regulates vascular permeability and endothelial barrier function.
• Promotes endothelial cell survival, proliferation, and migration.
• Involved in bone formation and osteogenesis through oxygen sensing.
• Plays a role in dental pulp vascularization and repair.
• Contributes to tumor angiogenesis and cancer progression.
• Mediates responses to shear stress and microvascular remodeling.
• Implicated in inflammatory and immune responses.
• Target for anti-angiogenic drugs in oncology and ophthalmology.
• Provides a model for studying signal transduction and gene regulation.
What Happens During cellular response to vascular endothelial growth factor stimulus?
VEGF Binding and Receptor Activation
In simple terms: VEGF binds to receptors on the cell surface, switching them on.
The response begins when VEGF ligands, such as VEGFA, bind to VEGF receptors (VEGFR1/FLT1, VEGFR2/KDR) on the plasma membrane. This binding induces receptor dimerization and autophosphorylation, activating intrinsic tyrosine kinase activity. Neuropilin co-receptors (NRP1, NRP2) enhance ligand binding and modulate signaling specificity. This initial step is critical for translating the extracellular VEGF stimulus into intracellular signals.
Downstream Signaling Cascades
In simple terms: Activated receptors trigger a relay of signals inside the cell.
Activated VEGFR2 phosphorylates adaptor proteins, leading to activation of the MAPK/ERK pathway, which promotes proliferation, and the PI3K/AKT pathway, which supports survival and migration. Phospholipase C gamma (PLCγ) is also activated, leading to calcium mobilization and activation of protein kinase C. These cascades amplify the signal and coordinate diverse cellular outcomes.
Cytoskeletal Rearrangement and Cell Migration
In simple terms: The cell changes shape and moves toward the stimulus.
VEGF signaling induces actin cytoskeletal reorganization, formation of stress fibers, and focal adhesion turnover, enabling endothelial cell migration. Integrins, particularly β3-integrin, modulate VEGF-A-dependent permeability and migration. This migratory response is essential for sprouting angiogenesis and vascular repair.
Gene Expression and Secretion
In simple terms: The cell turns genes on or off and releases factors.
VEGF stimulation activates transcription factors such as NF-κB and HIF-1α, leading to changes in gene expression that support angiogenesis, including upregulation of matrix metalloproteinases and adhesion molecules. Cells also increase secretion of cytokines and growth factors, contributing to the angiogenic microenvironment.
Feedback Regulation and Termination
In simple terms: The response is dampened to prevent excessive signaling.
VEGFR1 (FLT1) acts as a decoy receptor, sequestering VEGF and attenuating VEGFR2 signaling. Internalization and degradation of receptor-ligand complexes, as well as phosphatase-mediated dephosphorylation, terminate the response. Dysregulation of these feedback mechanisms can lead to pathological angiogenesis.
Key Genes Involved in GO:0035924 cellular response to vascular endothelial growth factor stimulus
The following genes and proteins are central to the cellular response to VEGF and are frequently studied in this context.
| Gene | Major Role | Research Relevance |
|---|---|---|
| VEGFA | Primary ligand that binds VEGFR2 to initiate signaling | Target for anti-angiogenic therapy; knockout models show vascular defects |
| KDR (VEGFR2) | Main receptor tyrosine kinase mediating VEGF responses | Key target for small molecule inhibitors; essential for endothelial function |
| FLT1 (VEGFR1) | Decoy receptor that modulates VEGF availability | Regulates angiogenesis; soluble form used as biomarker |
| NRP1 | Co-receptor enhancing VEGF binding to VEGFR2 | Modulates neuronal and vascular development |
| NRP2 | Co-receptor for VEGF and semaphorins | Involved in lymphangiogenesis and tumor progression |
| PLCG1 | Mediates calcium signaling downstream of VEGFR2 | Mutations affect vascular permeability |
| PIK3CA | Catalytic subunit of PI3K, activates AKT | Promotes survival and migration; often mutated in cancer |
| MAPK1 (ERK2) | Kinase in MAPK cascade, drives proliferation | Readout of VEGF-induced proliferation |
| MAPK3 (ERK1) | Kinase in MAPK cascade, drives proliferation | Readout of VEGF-induced proliferation |
| AKT1 | Serine/threonine kinase promoting survival | Mediates anti-apoptotic effects of VEGF |
| SRC | Non-receptor tyrosine kinase, modulates cytoskeleton | Regulates vascular permeability |
| PTK2 (FAK) | Focal adhesion kinase, involved in migration | Required for VEGF-induced migration |
| ITGB3 | Integrin β3, regulates permeability and adhesion | Modulates VEGF-A-dependent permeability |
| HIF1A | Transcription factor induced by hypoxia, upregulates VEGFA | Links oxygen sensing to VEGF response |
| NOS3 (eNOS) | Endothelial nitric oxide synthase, produces NO | Mediates vasodilation and permeability |
| CAV1 | Caveolin-1, organizes signaling microdomains | Regulates VEGFR2 internalization |
| PTPN11 (SHP2) | Phosphatase that modulates VEGFR2 signaling | Feedback regulation of angiogenesis |
How Is cellular response to vascular endothelial growth factor stimulus Regulated?
The cellular response to VEGF is tightly regulated at multiple levels. Oxygen tension controls VEGFA expression via HIF-1α, ensuring that angiogenesis matches metabolic demand. Shear stress from blood flow modulates VEGFR2 expression and signaling, contributing to vascular remodeling. Negative feedback loops involving VEGFR1 and phosphatases prevent excessive signaling. Additionally, microRNAs and epigenetic modifications fine-tune the response. Dysregulation of these control mechanisms underlies various vascular pathologies.
cellular response to vascular endothelial growth factor stimulus and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| VEGFA | Tumor angiogenesis, diabetic retinopathy | Knockout mouse, overexpression in endothelial cells |
| KDR | Cancer, vascular malformations | Kinase-dead knock-in, conditional knockout |
| FLT1 | Preeclampsia, cancer | Soluble FLT1 overexpression, knockout |
| HIF1A | Ischemia, cancer | Point mutation (P402A/P577A) to block degradation |
| ITGB3 | Glanzmann thrombasthenia, permeability disorders | Knockout, point mutation |
Cancer and Tumor Angiogenesis
VEGF signaling is a major driver of tumor angiogenesis, supplying nutrients and oxygen to growing tumors. Overexpression of VEGFA and VEGFR2 correlates with poor prognosis in many cancers. Anti-VEGF therapies, such as bevacizumab, are used clinically but resistance often develops. Studying GO:0035924 helps identify novel targets to overcome resistance.
Ocular Neovascularization
In diabetic retinopathy and age-related macular degeneration, excessive VEGF signaling leads to pathological blood vessel growth and leakage, causing vision loss. Anti-VEGF injections are standard treatment, highlighting the importance of understanding this response.
Cardiovascular and Metabolic Disorders
VEGF is critical for collateral vessel formation after ischemia, but dysregulated signaling contributes to atherosclerosis and edema. Shear stress-mediated VEGF responses are important for vascular adaptation. Targeting VEGF signaling requires careful balance to avoid adverse effects.
Bone and Dental Disorders
VEGF plays a role in bone formation and dental pulp vascularization. Impaired VEGF signaling is associated with delayed fracture healing and pulp necrosis. Understanding these processes may inform regenerative strategies.
From cellular response to vascular endothelial growth factor stimulus-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X mediate VEGF-induced migration? | Knockout of gene X in endothelial cells followed by VEGF stimulation |
| Does a specific phosphorylation site on VEGFR2 control permeability? | Point mutation (e.g., Y1175F) knock-in in KDR |
| Can a reporter track VEGF signaling in vivo? | Knock-in of fluorescent reporter downstream of VEGF response element |
| Does overexpression of VEGFA drive tumor angiogenesis? | Overexpression of VEGFA in cancer cell lines or mouse models |
| What is the role of a lncRNA in VEGF response? | CRISPR interference (CRISPRi) knockdown followed by RNA-seq |
| Can we identify novel regulators of VEGF signaling? | Genome-wide CRISPR knockout library screening |
How to Study the cellular response to vascular endothelial growth factor stimulus Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Changes in mRNA levels | Identify VEGF-induced transcriptional programs |
| Phosphoproteomics | Changes in protein phosphorylation | Map signaling pathways downstream of VEGFR2 |
| Live-cell imaging | Cell migration, receptor trafficking | Visualize dynamic responses to VEGF |
| CRISPR knockout screen | Gene essentiality for VEGF response | Discover novel regulators of angiogenesis |
| CRISPR activation screen | Gain-of-function effects | Identify genes that enhance VEGF signaling |
| Proximity ligation assay | Protein-protein interactions | Detect VEGFR2 complex formation |
| Calcium imaging | Intracellular calcium flux | Measure PLCγ activation |
| Wound healing assay | Cell migration | Assess VEGF-induced motility |
Transcriptomic Profiling
RNA-seq after VEGF stimulation reveals global changes in gene expression, identifying downstream targets and pathways. Time-course experiments capture immediate-early and late responses. Single-cell RNA-seq can resolve heterogeneity in endothelial cell populations.
Proteomic and Phosphoproteomic Analysis
Mass spectrometry-based proteomics quantifies changes in protein abundance and phosphorylation upon VEGF stimulation. This identifies activated signaling nodes and potential drug targets. Phosphoproteomics is particularly useful for mapping kinase cascades.
Imaging and Live-Cell Assays
Fluorescence microscopy and live-cell imaging track receptor internalization, cytoskeletal dynamics, and cell migration in response to VEGF. FRET biosensors can monitor kinase activity in real time. These methods provide spatial and temporal resolution.
Functional Genomics Screens
CRISPR knockout or activation screens coupled with VEGF-dependent phenotypes (e.g., proliferation, migration) identify novel regulators. Pooled screens with next-generation sequencing enable unbiased discovery. Validation is performed with individual sgRNAs.
How CRISPR Can Be Used to Study GO:0035924 cellular response to vascular endothelial growth factor stimulus
Knockout
CRISPR knockout of genes such as KDR or VEGFA in endothelial cells abolishes VEGF-induced signaling, providing causal evidence for their role. Knockout models are used to study angiogenesis, permeability, and gene expression changes. Conditional knockout in mice allows tissue-specific analysis.
Point Mutation
Introducing point mutations (e.g., kinase-dead VEGFR2 or phosphorylation site mutants) via CRISPR knock-in enables precise dissection of signaling nodes. These models help distinguish between different downstream branches. They are valuable for drug resistance studies.
Knock-in
Knock-in of reporter genes (e.g., GFP) or epitope tags at endogenous loci allows real-time tracking of VEGF signaling components. Tagged knock-in of VEGFR2 facilitates proteomic and imaging studies. This approach preserves endogenous regulation.
Overexpression
CRISPR activation (CRISPRa) or transgenic overexpression of VEGFA or constitutively active VEGFR2 drives angiogenesis and tumor growth in models. Overexpression models are used to study gain-of-function effects and test inhibitors. They complement loss-of-function studies.
How EDITGENE Supports cellular response to vascular endothelial growth factor stimulus Research
Researchers studying cellular response to vascular endothelial growth factor stimulus-related genes often need to determine whether a candidate gene is causally involved in VEGF signaling, and to dissect the precise molecular mechanisms. EDITGENE provides a comprehensive suite of CRISPR-based services to accelerate this research, from gene knockout to precise point mutations and library screening.
Contact EDITGENE today to design your custom CRISPR model for cellular response to vascular endothelial growth factor stimulus research.
Frequently Asked Questions About cellular response to vascular endothelial growth factor stimulus
What is GO:0035924?
GO:0035924 is the Gene Ontology term for cellular response to vascular endothelial growth factor stimulus, describing all cellular changes triggered by VEGF.
What genes are involved in cellular response to VEGF?
Key genes include VEGFA, KDR (VEGFR2), FLT1 (VEGFR1), NRP1, and downstream effectors like MAPK1 and AKT1.
What is the function of VEGF signaling?
VEGF signaling promotes angiogenesis, vascular permeability, endothelial cell survival, and migration.
How is VEGF signaling regulated?
It is regulated by oxygen tension via HIF-1α, shear stress, and feedback loops involving VEGFR1 and phosphatases.
What diseases are associated with VEGF signaling?
Cancer, diabetic retinopathy, cardiovascular disease, and bone disorders are linked to dysregulated VEGF signaling.
What are the main downstream pathways of VEGFR2?
The MAPK/ERK and PI3K/AKT pathways are major downstream cascades activated by VEGFR2.
How can I study VEGF signaling using CRISPR?
CRISPR knockout, knock-in, and overexpression models allow functional dissection of VEGF response genes.
What is the role of VEGFR1 in VEGF response?
VEGFR1 acts as a decoy receptor that sequesters VEGF and modulates VEGFR2 signaling.
What methods are used to measure VEGF-induced gene expression?
RNA-seq, qPCR, and reporter assays are commonly used to measure transcriptional changes.
What is the role of shear stress in VEGF response?
Shear stress from blood flow modulates VEGFR2 expression and microvascular remodeling.
Conclusion
The cellular response to vascular endothelial growth factor stimulus (GO:0035924) is a fundamental biological process that governs angiogenesis, vascular permeability, and cell survival. Its dysregulation is central to cancer, ocular diseases, and cardiovascular disorders, making it a prime target for therapeutic intervention. Advances in CRISPR-based models and functional genomics are enabling precise dissection of the underlying mechanisms. EDITGENE offers comprehensive services to support researchers in this field, from knockout to library screening, accelerating discoveries that may translate into new treatments.
References
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- 6. Wang Y et al.. 2007. Oxygen sensing and osteogenesis.. Ann N Y Acad Sci 1117:1-11 PMID: 18056033
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