GO:0036323 vascular endothelial growth factor receptor-1 signaling pathway: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0036323 describes the molecular signaling cascade initiated by ligand binding to VEGFR-1 (FLT1), a receptor tyrosine kinase that regulates angiogenesis, inflammation, and tissue repair.
• VEGFR-1 exists as both a membrane-bound receptor and a soluble decoy (sFlt-1), with dual roles in promoting and inhibiting angiogenesis depending on context.
• VEGFR-1 tyrosine kinase signaling is essential for pathological angiogenesis in models such as the surgical sponge model and for healing in DSS-induced colitis.
• Dysregulated VEGFR-1 signaling contributes to pulmonary fibrosis, preeclampsia, and cancer progression, making it a therapeutic target.
• Key molecular players include VEGF-A, VEGF-B, PlGF, NRP1, and downstream effectors such as PI3K/AKT and MAPK.
• CRISPR-based knockout, point mutation, knock-in, and overexpression models are powerful tools to dissect VEGFR-1 signaling in health and disease.
Description
The vascular endothelial growth factor receptor-1 (VEGFR-1), also known as FLT1, is a receptor tyrosine kinase that binds VEGF-A, VEGF-B, and placental growth factor (PlGF). The signaling pathway initiated by VEGFR-1 (GO:0036323) is a critical regulator of angiogenesis, vascular permeability, and inflammation. Unlike VEGFR-2, VEGFR-1 has weak tyrosine kinase activity in endothelial cells but plays essential roles in development, pathological angiogenesis, and immune cell recruitment. Understanding this pathway is vital for researchers studying cancer, fibrosis, and pregnancy-related disorders. This article integrates authoritative QuickGO annotation and verified PubMed literature to provide a comprehensive overview of VEGFR-1 signaling, its components, disease relevance, and experimental approaches.
vascular endothelial growth factor receptor-1 signaling pathway At A Glance
| GO ID | GO:0036323 |
|---|---|
| GO term | vascular endothelial growth factor receptor-1 signaling pathway |
| Ontology | biological_process |
| Synonym | FLT1 signaling pathway, VEGFR-1 signaling pathway, VEGFR1 signaling pathway |
| Major function | Regulation of angiogenesis, vascular permeability, inflammation, and cell survival |
| Ligands | VEGF-A, VEGF-B, PlGF |
| Receptor | VEGFR-1 (FLT1), including soluble sFlt-1 |
| Downstream effectors | PI3K/AKT, MAPK, PLCγ, Src |
What Is GO:0036323?
GO:0036323, vascular endothelial growth factor receptor-1 signaling pathway, is defined as the series of molecular signals initiated by a ligand binding to VEGFR-1 on the cell surface, leading to regulation of downstream cellular processes such as transcription. This pathway includes ligand-receptor interaction, receptor dimerization and autophosphorylation, activation of intracellular signaling cascades (e.g., PI3K/AKT, MAPK), and modulation of gene expression.
Why Is vascular endothelial growth factor receptor-1 signaling pathway Important in Cell Biology?
VEGFR-1 signaling is a central node in vascular biology and disease. It modulates angiogenesis during development and in pathological conditions such as cancer, fibrosis, and preeclampsia. The pathway also influences immune cell function, including Treg accumulation in colitis healing. Because of its dual pro- and anti-angiogenic roles, VEGFR-1 is a prime target for therapeutic intervention and a focus of intense research.
• Regulates physiological and pathological angiogenesis.
• Modulates vascular permeability and endothelial cell survival.
• Involved in pulmonary fibrosis and lung alveolar repair.
• Contributes to preeclampsia via sFlt-1/PlGF imbalance.
• Facilitates healing in DSS-induced colitis by Treg accumulation.
• Enhances angiogenesis in surgical sponge models.
• Required for endothelial cell adhesion to soluble VEGFR-1.
• Serves as a therapeutic target in cancer and inflammatory diseases.
• Plays a role in immune cell recruitment and inflammation.
• Provides a model for studying receptor tyrosine kinase signaling.
What Happens During vascular endothelial growth factor receptor-1 signaling pathway?
Ligand Binding and Receptor Activation
In simple terms: Growth factors bind to VEGFR-1 on the cell surface, turning the receptor on.
The pathway begins when ligands such as VEGF-A, VEGF-B, or PlGF bind to the extracellular domain of VEGFR-1 (FLT1). This binding induces receptor dimerization and autophosphorylation of tyrosine residues in the intracellular kinase domain, initiating downstream signaling. Soluble VEGFR-1 (sFlt-1) can sequester ligands, acting as a decoy to modulate pathway activity.
Intracellular Signaling Cascades
In simple terms: Activated VEGFR-1 triggers a relay of proteins inside the cell that carry the signal forward.
Phosphorylated VEGFR-1 recruits adaptor proteins and enzymes, activating pathways such as PI3K/AKT, MAPK, and PLCγ. These cascades regulate endothelial cell proliferation, migration, and survival. In some contexts, VEGFR-1 signaling can also activate Src family kinases and modulate cytoskeletal dynamics.
Regulation of Downstream Cellular Processes
In simple terms: The signal reaches the nucleus and changes which genes are turned on or off.
Activated signaling pathways lead to changes in gene expression that promote angiogenesis, inflammation, or tissue repair. For example, VEGFR-1 signaling enhances angiogenesis in surgical sponge models and facilitates Treg accumulation in colitis. The pathway also cross-talks with other signaling networks, including NRF2 and LAT1, to modulate oxidative stress and sFlt-1/PlGF balance.
Context-Dependent Outcomes
In simple terms: The same pathway can have opposite effects depending on the tissue and situation.
VEGFR-1 signaling exhibits dual functions: it can promote angiogenesis in some settings (e.g., surgical sponge model) but inhibit it in others via sFlt-1. In pulmonary fibrosis, VEGFR-1 tyrosine kinase signaling contributes to disease progression, while in colitis it supports healing. This context dependence is critical for therapeutic targeting.
Key Genes Involved in GO:0036323 vascular endothelial growth factor receptor-1 signaling pathway
The following genes and proteins are central to VEGFR-1 signaling, as supported by published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| FLT1 (VEGFR-1) | Receptor tyrosine kinase; binds VEGF-A, VEGF-B, PlGF | Core receptor; target for KO, point mutation, and knock-in studies |
| VEGFA | Primary ligand for VEGFR-1 and VEGFR-2 | Key regulator of angiogenesis; overexpression models |
| VEGFB | Ligand for VEGFR-1 | Modulates lipid metabolism and angiogenesis |
| PGF (PlGF) | Ligand for VEGFR-1 | Involved in pathological angiogenesis and preeclampsia |
| NRP1 | Co-receptor for VEGF and semaphorins | Required for endothelial cell adhesion to sFlt-1 |
| KDR (VEGFR-2) | Receptor tyrosine kinase for VEGF | Cross-talks with VEGFR-1; KO models |
| PIK3CA | PI3K catalytic subunit | Downstream effector of VEGFR-1; point mutation models |
| AKT1 | Serine/threonine kinase | Mediates survival signals; overexpression studies |
| MAPK1 (ERK2) | Mitogen-activated protein kinase | Regulates proliferation; KO and point mutation models |
| PLCG1 | Phospholipase C gamma 1 | Downstream of VEGFR-1; knock-in reporters |
| SRC | Proto-oncogene tyrosine kinase | Modulates cytoskeletal signaling |
| HIF1A | Hypoxia-inducible factor 1-alpha | Regulates VEGF expression; KO models |
| NRF2 (NFE2L2) | Transcription factor | Controls sFlt-1/PlGF balance and oxidative stress |
| SLC7A5 (LAT1) | Amino acid transporter | Part of LAT1-NRF2 axis in preeclampsia |
| FOXP3 | Transcription factor for Tregs | Linked to VEGFR-1-mediated Treg accumulation |
| CD4 | T cell co-receptor | Marker for Tregs in colitis healing |
| PECAM1 (CD31) | Endothelial cell adhesion molecule | Used as endothelial marker in angiogenesis assays |
| ACTA2 | Smooth muscle actin | Marker for fibrosis in pulmonary models |
How Is vascular endothelial growth factor receptor-1 signaling pathway Regulated?
VEGFR-1 signaling is tightly regulated at multiple levels. Soluble VEGFR-1 (sFlt-1) acts as a decoy receptor, sequestering VEGF and PlGF to dampen signaling. The LAT1-NRF2 axis controls sFlt-1/PlGF imbalance and oxidative stress in preeclampsia. Neuropilin-1 (NRP1) is required for endothelial cell adhesion to soluble VEGFR-1, modulating pathway activity. Additionally, receptor internalization, degradation, and phosphatase-mediated dephosphorylation provide negative feedback.
vascular endothelial growth factor receptor-1 signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| FLT1 | Pulmonary fibrosis | Knockout mouse; bleomycin-induced fibrosis model |
| FLT1 | Preeclampsia | Overexpression of sFlt-1 in pregnant mice |
| FLT1 | Colitis | DSS-induced colitis in VEGFR-1 KO mice |
| VEGFA | Cancer angiogenesis | Tumor xenograft with VEGF overexpression |
| NRP1 | Endothelial adhesion | NRP1 knockout endothelial cells |
Pulmonary Fibrosis and Lung Repair
VEGFR-1 signaling is implicated in pulmonary fibrosis. Targeting the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis. In bleomycin-induced pulmonary fibrosis, VEGFR-1 tyrosine kinase signaling contributes to disease pathogenesis, suggesting that inhibition may be therapeutic.
Preeclampsia
Preeclampsia is associated with an imbalance in sFlt-1 and PlGF. The LAT1-NRF2 axis controls this imbalance and oxidative stress, linking VEGFR-1 signaling to disease severity. Elevated sFlt-1 sequesters VEGF and PlGF, leading to endothelial dysfunction.
Inflammatory Bowel Disease
VEGFR-1 tyrosine kinase signaling facilitates healing of DSS-induced colitis by promoting Treg accumulation in ulcer areas. This highlights a protective role for VEGFR-1 in intestinal inflammation.
Cancer and Angiogenesis
VEGFR-1 signaling enhances angiogenesis in pathological settings, including tumor growth. Positive and negative regulation by soluble VEGFR-1 underscores its complex role in cancer. Targeting VEGFR-1 may inhibit tumor angiogenesis.
From vascular endothelial growth factor receptor-1 signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does VEGFR-1 kinase activity drive fibrosis? | Kinase-dead point mutation knock-in mouse |
| What is the role of sFlt-1 in preeclampsia? | Inducible overexpression of sFlt-1 |
| How does VEGFR-1 signaling affect Tregs in colitis? | Conditional knockout in T cells |
| Can VEGFR-1 be targeted for angiogenesis? | Endothelial-specific knockout |
| What downstream effectors mediate VEGFR-1 signaling? | Phospho-proteomics in knockout cells |
| Does NRP1 modulate VEGFR-1 adhesion? | NRP1 knockout endothelial cells |
How to Study the vascular endothelial growth factor receptor-1 signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Transcriptional changes | Identify VEGFR-1 target genes |
| Phosphoproteomics | Phosphorylation events | Map signaling cascades |
| Tube formation assay | Angiogenesis in vitro | Test VEGFR-1 ligands/inhibitors |
| Immunohistochemistry | Protein localization | Assess VEGFR-1 in tissues |
| CRISPR knockout | Gene function | Validate pathway components |
| Western blot | Protein expression/phosphorylation | Confirm pathway activation |
| ELISA | sFlt-1/PlGF levels | Preeclampsia diagnostics |
| Flow cytometry | Immune cell populations | Treg accumulation in colitis |
Transcriptomics and RNA-seq
RNA sequencing can reveal gene expression changes downstream of VEGFR-1 activation, identifying target genes involved in angiogenesis and inflammation.
Proteomics and Phosphoproteomics
Mass spectrometry-based proteomics can map phosphorylation events and protein-protein interactions in VEGFR-1 signaling, uncovering novel effectors.
Imaging and Angiogenesis Assays
Endothelial tube formation, sprouting assays, and intravital imaging visualize VEGFR-1-mediated angiogenesis in vivo.
CRISPR Screening
Genome-wide CRISPR knockout screens can identify genes that modulate VEGFR-1 signaling, providing unbiased insights into pathway regulation.
How CRISPR Can Be Used to Study GO:0036323 vascular endothelial growth factor receptor-1 signaling pathway
Knockout
CRISPR knockout of FLT1 or downstream effectors (e.g., PIK3CA, AKT1) can abolish VEGFR-1 signaling, revealing essential components and phenotypic outcomes in angiogenesis and inflammation.
Point Mutation
Introducing kinase-dead or phospho-null point mutations in FLT1 via CRISPR can dissect the specific contribution of tyrosine kinase activity versus ligand sequestration.
Knock-in
Knock-in of fluorescent tags (e.g., GFP) or epitope tags into the FLT1 locus enables real-time imaging and biochemical tracking of VEGFR-1 in live cells.
Overexpression
CRISPR activation (CRISPRa) or transgenic overexpression of VEGFA, PGF, or sFlt-1 can model pathological states such as preeclampsia and tumor angiogenesis.
How EDITGENE Supports vascular endothelial growth factor receptor-1 signaling pathway Research
Researchers studying vascular endothelial growth factor receptor-1 signaling pathway-related genes often need to determine whether a candidate gene is causally involved in pathway regulation, disease progression, or therapeutic response. EDITGENE provides comprehensive CRISPR-based services to accelerate this discovery.
Contact EDITGENE today to design your custom CRISPR model for vascular endothelial growth factor receptor-1 signaling pathway research.
Frequently Asked Questions About vascular endothelial growth factor receptor-1 signaling pathway
What is GO:0036323?
GO:0036323 is the Gene Ontology term for the vascular endothelial growth factor receptor-1 signaling pathway, describing the molecular signals initiated by ligand binding to VEGFR-1.
What genes are involved in VEGFR-1 signaling?
Key genes include FLT1 (VEGFR-1), VEGFA, VEGFB, PGF, NRP1, PIK3CA, AKT1, MAPK1, and PLCG1.
What is the role of VEGFR-1 in angiogenesis?
VEGFR-1 signaling regulates angiogenesis by promoting endothelial cell survival, migration, and tube formation, though it can also inhibit angiogenesis via soluble sFlt-1.
How is VEGFR-1 signaling dysregulated in preeclampsia?
In preeclampsia, an imbalance in sFlt-1 and PlGF leads to excessive sequestration of VEGF, causing endothelial dysfunction; the LAT1-NRF2 axis controls this imbalance.
What diseases are associated with VEGFR-1 signaling?
Pulmonary fibrosis, preeclampsia, inflammatory bowel disease, and cancer are linked to VEGFR-1 signaling.
What are the downstream effectors of VEGFR-1?
PI3K/AKT, MAPK, PLCγ, and Src family kinases are major downstream effectors.
How can CRISPR be used to study VEGFR-1 signaling?
CRISPR knockout, point mutation, knock-in, and overexpression models allow precise dissection of VEGFR-1 function in vitro and in vivo.
What is soluble VEGFR-1 (sFlt-1)?
sFlt-1 is a soluble decoy receptor that binds VEGF and PlGF, preventing their interaction with membrane-bound VEGFR-1 and modulating angiogenesis.
Is VEGFR-1 a therapeutic target?
Yes, VEGFR-1 is a target in cancer, fibrosis, and preeclampsia, with inhibitors and antibodies under investigation.
What model systems are used to study VEGFR-1 signaling?
Common models include endothelial cell cultures, knockout mice, DSS-induced colitis, bleomycin-induced fibrosis, and surgical sponge angiogenesis models.
Conclusion
GO:0036323, the vascular endothelial growth factor receptor-1 signaling pathway, is a critical regulator of angiogenesis, inflammation, and tissue repair. Its dual roles and context-dependent effects make it a rich area for research and therapeutic targeting. Leveraging CRISPR-based models and multi-omics approaches will continue to unravel its complexity and translate findings into clinical advances.
References
- 1. Cao Z et al.. 2016. Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis.. Nat Med 22(2):154-62 PMID: 26779814
- 2. Granitzer S et al.. 2025. LAT1-NRF2 axis controls sFlt-1/PlGF imbalance and oxidative stress in preeclampsia.. Nat Commun 16(1):9112 PMID: 41087351
- 3. Colotti G et al.. 2022. Neuropilin-1 is required for endothelial cell adhesion to soluble vascular endothelial growth factor receptor 1.. FEBS J 289(1):183-198 PMID: 34252269
- 4. Failla CM et al.. 2018. Positive and Negative Regulation of Angiogenesis by Soluble Vascular Endothelial Growth Factor Receptor-1.. Int J Mol Sci 19(5) PMID: 29702562
- 5. Amano H et al.. 2019. The role of vascular endothelial growth factor receptor 1 tyrosine kinase signaling in bleomycin-induced pulmonary fibrosis.. Biomed Pharmacother 117:109067 PMID: 31176171
- 6. Shibuya M. 2001. Structure and dual function of vascular endothelial growth factor receptor-1 (Flt-1).. Int J Biochem Cell Biol 33(4):409-20 PMID: 11312109
- 7. Park K et al.. 2016. Vascular endothelial growth factor receptor-1 (VEGFR-1) signaling enhances angiogenesis in a surgical sponge model.. Biomed Pharmacother 78:140-149 PMID: 26898435
- 8. Betto T et al.. 2019. Vascular endothelial growth factor receptor 1 tyrosine kinase signaling facilitates healing of DSS-induced colitis by accumulation of Tregs in ulcer area.. Biomed Pharmacother 111:131-141 PMID: 30579252
