GO:1904995 negative regulation of leukocyte adhesion to vascular endothelial cell: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1904995 describes any process that stops, prevents, or reduces the frequency, rate, or extent of leukocyte adhesion to vascular endothelial cells, a critical checkpoint in inflammation and immune surveillance [1,2].
• Key molecular players include angiopoietin-1, VEGF, sphingosine-1-phosphate, MEF2C, KLF2, ZNF667, P-selectin, and Csk, which act through NF-kB, Src family kinases, and adhesion molecule downregulation [1,3,4,5].
• Dysregulation of this process contributes to chronic inflammatory diseases, atherosclerosis, and cancer metastasis, making it a therapeutic target [6,8].
• Experimental models for studying GO:1904995 include endothelial-leukocyte adhesion assays, flow chamber systems, and CRISPR-engineered endothelial cell lines with gene knockouts or point mutations [4,5].
• CRISPR knockout, knock-in, and overexpression models enable causal dissection of genes such as MEF2C, KLF2, and ZNF667 in leukocyte adhesion [3,5].
• EDITGENE provides customized CRISPR cell models and library screening to accelerate research on negative regulation of leukocyte adhesion.
Description
Leukocyte adhesion to vascular endothelial cells is a fundamental step in the inflammatory response, allowing immune cells to exit the bloodstream and reach sites of injury or infection. However, excessive or inappropriate adhesion contributes to tissue damage in chronic inflammatory diseases, atherosclerosis, and ischemia-reperfusion injury [1,2]. The Gene Ontology term GO:1904995, negative regulation of leukocyte adhesion to vascular endothelial cell, encompasses any process that stops, prevents, or reduces the frequency, rate, or extent of this adhesion event. Understanding the molecular mechanisms that negatively regulate leukocyte adhesion is essential for developing anti-inflammatory therapies and for deciphering how endothelial cells maintain vascular homeostasis [3,5]. This article integrates authoritative QuickGO data with published literature to provide a research-grade overview of GO:1904995, covering its definition, biological significance, key genes, and experimental approaches for investigation.
negative regulation of leukocyte adhesion to vascular endothelial cell At A Glance
| GO ID | GO:1904995 |
|---|---|
| GO term | negative regulation of leukocyte adhesion to vascular endothelial cell |
| Ontology | biological_process |
| Synonym | down regulation of leukocyte adhesion to vascular endothelial cell; down-regulation of leukocyte adhesion to vascular endothelial cell; downregulation of leukocyte adhesion to vascular endothelial cell; inhibition of leukocyte adhesion to vascular endothelial cell |
| Major function | Suppression of leukocyte adhesion to endothelial cells, thereby limiting inflammatory cell recruitment |
| Related processes | Leukocyte adhesion, endothelial cell activation, inflammation, immune cell extravasation |
| Cellular location | Vascular endothelial cell surface and intracellular signaling compartments |
| Key regulators | Angiopoietin-1, VEGF, S1P, MEF2C, KLF2, ZNF667, Csk, P-selectin |
What Is GO:1904995?
GO:1904995 is a biological process term defined as any process that stops, prevents, or reduces the frequency, rate, or extent of leukocyte adhesion to vascular endothelial cell. It includes molecular events that inhibit the tethering, rolling, firm adhesion, or transmigration of leukocytes on endothelial surfaces. Synonyms include down regulation, down-regulation, downregulation, and inhibition of leukocyte adhesion to vascular endothelial cell.
Why Is negative regulation of leukocyte adhesion to vascular endothelial cell Important in Cell Biology?
Negative regulation of leukocyte adhesion to vascular endothelial cells is crucial for preventing excessive inflammation and maintaining vascular integrity. Dysregulation of this process is implicated in chronic inflammatory diseases, atherosclerosis, and cancer metastasis, where uncontrolled leukocyte adhesion exacerbates tissue damage or promotes tumor cell dissemination [6,8]. Understanding the molecular brakes on leukocyte adhesion can reveal therapeutic targets for anti-inflammatory interventions and improve outcomes in diseases such as ischemia-reperfusion injury and autoimmune disorders [1,5].
• Prevents excessive leukocyte recruitment that leads to tissue damage in chronic inflammation.
• Maintains endothelial barrier function and vascular homeostasis.
• Limits atherosclerosis progression by reducing monocyte adhesion to activated endothelium.
• Modulates immune surveillance and response to infection.
• Influences cancer metastasis by affecting tumor cell-leukocyte-endothelial interactions.
• Provides targets for anti-inflammatory drug development, such as angiopoietin-1 mimetics.
• Regulates ischemia-reperfusion injury in organs like skin and heart.
• Involved in sepsis-associated endothelial dysfunction.
• Key to understanding leukocyte extravasation in autoimmune diseases.
• Offers biomarkers for endothelial dysfunction and inflammation.
What Happens During negative regulation of leukocyte adhesion to vascular endothelial cell?
Inhibition of Adhesion Molecule Expression
In simple terms: Endothelial cells can reduce the amount of sticky proteins on their surface, making it harder for leukocytes to attach.
Negative regulation of leukocyte adhesion often involves downregulation of adhesion molecules such as P-selectin, E-selectin, ICAM-1, and VCAM-1 on endothelial cells. For example, ZNF667 attenuates leukocyte-endothelial adhesion via downregulation of P-selectin in skin flap following remote limb ischemic preconditioning. Similarly, transcription factor MEF2C suppresses endothelial cell inflammation by regulating NF-kB and KLF2, leading to reduced adhesion molecule expression.
Modulation of Chemokine and Cytokine Signaling
In simple terms: Chemical signals that attract leukocytes can be blocked, preventing them from stopping at the endothelium.
Inflammatory cytokines and chemokines promote leukocyte adhesion by activating endothelial cells. Negative regulation can occur through inhibition of NF-kB signaling, as seen with MEF2C overexpression, which reduces cytokine-induced adhesion molecule expression. Additionally, sphingosine-1-phosphate (S1P) signaling can modulate endothelial function to suppress leukocyte adhesion.
Regulation of Cytoskeletal Dynamics and Junctional Integrity
In simple terms: The endothelial cell skeleton and cell-cell junctions can be tightened to prevent leukocytes from squeezing through.
Csk controls leukocyte extravasation via local regulation of Src family kinases and cortactin signaling, affecting endothelial cytoskeletal rearrangements and junctional stability. By modulating Src activity, Csk can negatively regulate the opening of endothelial junctions required for leukocyte transmigration.
Induction of Anti-inflammatory Transcription Factors
In simple terms: Certain master switches in endothelial cells can turn on anti-inflammatory genes and turn off pro-adhesive ones.
KLF2 is a shear-stress-induced transcription factor that suppresses endothelial inflammation and adhesion molecule expression. MEF2C regulates KLF2 and NF-kB, thereby promoting an anti-adhesive endothelial phenotype. Angiopoietin-1 also induces anti-inflammatory signaling through nuclear receptor-77, reducing leukocyte adhesion.
Inhibition of Leukocyte Integrin Activation
In simple terms: Even if leukocytes get close, their own sticky proteins can be kept in an inactive state.
Negative regulation can also target leukocyte integrins. For instance, angiopoietin-1 and VEGF regulate leukocyte adhesion to endothelial cells via nuclear receptor-77, which may affect integrin activation on leukocytes. However, most described mechanisms focus on endothelial cell changes.
Key Genes Involved in GO:1904995 negative regulation of leukocyte adhesion to vascular endothelial cell
The following genes and proteins have been experimentally implicated in the negative regulation of leukocyte adhesion to vascular endothelial cells.
| Gene | Major Role | Research Relevance |
|---|---|---|
| ANGPT1 | Angiopoietin-1 reduces leukocyte adhesion via nuclear receptor-77 | Therapeutic target for anti-inflammatory strategies |
| VEGFA | VEGF modulates leukocyte adhesion through NR77 and endothelial activation | Implicated in vascular permeability and inflammation |
| MEF2C | Transcription factor suppressing NF-kB and inducing KLF2 | Key anti-inflammatory regulator in endothelium |
| KLF2 | Shear-stress-induced transcription factor inhibiting adhesion molecules | Master regulator of endothelial quiescence |
| ZNF667 | Downregulates P-selectin, attenuating leukocyte-endothelial adhesion | Protective in ischemia-reperfusion injury |
| SELP | P-selectin mediates leukocyte rolling; its downregulation reduces adhesion | Target of ZNF667 in skin flap protection |
| CSK | C-terminal Src kinase regulates Src family kinases and cortactin | Controls leukocyte extravasation via cytoskeletal signaling |
| SRC | Src family kinases promote endothelial junction opening | Inhibited by Csk to limit extravasation |
| CTTN | Cortactin involved in actin remodeling and junctional dynamics | Effector of Csk signaling in extravasation |
| NFKB1 | NF-kB promotes adhesion molecule expression; its inhibition reduces adhesion | Target of MEF2C-mediated suppression |
| S1PR1 | Sphingosine-1-phosphate receptor 1 enhances endothelial barrier function | Modulates leukocyte adhesion |
| MMP2 | Matrix metalloproteinase-2 affects endothelial-mononuclear cell interactions | Potential regulator of adhesion via matrix remodeling |
| MMP9 | Matrix metalloproteinase-9 involved in endothelial-mononuclear cell close encounters | Implicated in leukocyte adhesion and migration |
| RELN | Reelin modulates inflammatory responses and leukocyte adhesion | Anti-Reelin therapeutics under safety evaluation |
| 6-MSITC | 6-Methylsulfinylhexyl isothiocyanate suppresses leukocyte adhesion | Natural compound modulating endothelial function |
| ICAM1 | Intercellular adhesion molecule 1 mediates firm adhesion; its downregulation is negative regulation | Common endpoint in adhesion assays [1,3] |
| VCAM1 | Vascular cell adhesion molecule 1 mediates leukocyte adhesion; downregulation reduces adhesion | Target of anti-inflammatory signaling |
| SELE | E-selectin mediates rolling; its suppression contributes to negative regulation | Marker of endothelial activation |
How Is negative regulation of leukocyte adhesion to vascular endothelial cell Regulated?
The negative regulation of leukocyte adhesion to vascular endothelial cells is controlled by a network of signaling pathways. Angiopoietin-1 and VEGF regulate leukocyte adhesion through nuclear receptor-77, which modulates endothelial inflammatory responses. Sphingosine-1-phosphate signaling enhances endothelial barrier function and suppresses leukocyte adhesion. The transcription factor MEF2C suppresses endothelial inflammation by regulating NF-kB and KLF2, thereby reducing adhesion molecule expression. Csk locally regulates Src family kinases and cortactin signaling to control leukocyte extravasation. Additionally, ZNF667 downregulates P-selectin to attenuate leukocyte-endothelial adhesion in the context of remote limb ischemic preconditioning. These pathways converge on the suppression of adhesion molecules and the maintenance of endothelial junctional integrity.
negative regulation of leukocyte adhesion to vascular endothelial cell and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| ANGPT1 | Atherosclerosis, inflammation | Endothelial cell overexpression and leukocyte adhesion assay |
| ZNF667 | Ischemia-reperfusion injury | Skin flap model with remote limb ischemic preconditioning |
| MEF2C | Endothelial inflammation | Knockout and overexpression in HUVECs |
| CSK | Leukocyte extravasation in inflammation | Endothelial-specific knockout mouse |
| RELN | Chronic inflammatory diseases | Anti-Reelin antibody treatment in mouse models |
Atherosclerosis and Cardiovascular Disease
Excessive leukocyte adhesion to endothelial cells is a hallmark of early atherosclerosis. Negative regulation of this process by factors such as angiopoietin-1 and KLF2 helps maintain endothelial quiescence and reduces monocyte recruitment, thereby limiting plaque formation [1,3]. Matrix metalloproteinases also influence endothelial-mononuclear cell interactions in vascular disease.
Ischemia-Reperfusion Injury
In ischemia-reperfusion injury, leukocyte adhesion exacerbates tissue damage. ZNF667-mediated downregulation of P-selectin attenuates leukocyte-endothelial adhesion in skin flaps following remote limb ischemic preconditioning, suggesting a protective role for negative regulation. Similarly, Csk-mediated control of Src signaling may limit extravasation in reperfused tissues.
Chronic Inflammatory and Autoimmune Diseases
In chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, persistent leukocyte adhesion contributes to tissue destruction. Anti-Reelin therapeutic approaches are being evaluated for safety in chronic inflammatory diseases, highlighting the importance of modulating leukocyte adhesion. Sphingosine-1-phosphate signaling, which negatively regulates adhesion, is a target for immunomodulatory drugs.
Cancer Metastasis
Leukocyte-endothelial interactions can facilitate tumor cell dissemination. Matrix metalloproteinases and adhesion molecules are implicated in cancer metastasis, and negative regulation of leukocyte adhesion may reduce metastatic potential. Understanding these mechanisms could inform therapies that target the tumor microenvironment.
From negative regulation of leukocyte adhesion to vascular endothelial cell-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X negatively regulate leukocyte adhesion? | CRISPR knockout of gene X in endothelial cells followed by adhesion assay [3,5] |
| Does a point mutation in gene X affect its anti-adhesive function? | CRISPR point mutation knock-in in endothelial cells |
| Does overexpression of gene X reduce leukocyte adhesion? | Lentiviral overexpression in HUVECs [1,3] |
| Does tagging gene X reveal its localization during adhesion? | CRISPR knock-in of fluorescent tag |
| Which genes are essential for negative regulation? | Genome-wide CRISPR library screening in endothelial cells under inflammatory conditions |
| Does gene X regulate adhesion in vivo? | Endothelial-specific conditional knockout mouse [4,5] |
How to Study the negative regulation of leukocyte adhesion to vascular endothelial cell Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Static adhesion assay | Number of leukocytes adhered to endothelial cells | Screening for anti-adhesive genes [1,5] |
| Flow chamber assay | Leukocyte rolling and firm adhesion under shear stress | Physiological relevance of negative regulation |
| RNA-seq | Transcriptional changes in adhesion molecules and signaling | Identifying pathways regulated by MEF2C, KLF2 |
| Proteomics | Protein expression and post-translational modifications | Validating targets of Csk signaling |
| Immunofluorescence | Localization of adhesion molecules and junctional proteins | Visualizing P-selectin downregulation |
| CRISPR screening | Genes required for negative regulation | Unbiased discovery of novel regulators |
| Western blot | Protein levels of adhesion molecules and signaling intermediates | Confirming knockdown or overexpression [1,3] |
| ELISA | Soluble adhesion molecules in supernatant | Biomarker measurement |
Leukocyte-Endothelial Adhesion Assays
In vitro adhesion assays using fluorescently labeled leukocytes and activated endothelial cells are standard for quantifying adhesion. These assays can be combined with CRISPR knockout or overexpression to test the role of specific genes [1,3,5].
Flow Chamber Systems
Flow chambers simulate physiological shear stress and allow real-time visualization of leukocyte rolling, adhesion, and transmigration on endothelial monolayers. This method is ideal for studying dynamic regulation of adhesion.
Transcriptomic and Proteomic Profiling
RNA-seq and proteomics can identify changes in adhesion molecule expression and signaling pathways following genetic manipulation. For example, MEF2C regulation of NF-kB and KLF2 was dissected using transcriptomic approaches.
Imaging and Immunofluorescence
Confocal microscopy and immunofluorescence can visualize adhesion molecule localization, junctional integrity, and leukocyte-endothelial interactions. Tagged knock-in models enable tracking of specific proteins.
How CRISPR Can Be Used to Study GO:1904995 negative regulation of leukocyte adhesion to vascular endothelial cell
Knockout
CRISPR knockout of candidate genes in endothelial cells can determine whether they are necessary for negative regulation of leukocyte adhesion. For example, knocking out MEF2C or KLF2 would be expected to increase adhesion, confirming their anti-adhesive roles.
Point Mutation
Point mutations can dissect specific phosphorylation sites or functional domains. For instance, mutating Src phosphorylation sites in Csk or cortactin could reveal their role in extravasation.
Knock-in
Knock-in of fluorescent tags or reporter genes allows real-time tracking of proteins like P-selectin or ICAM-1 during leukocyte adhesion. This can be combined with live imaging to study dynamics.
Overexpression
Overexpression of anti-inflammatory genes such as ANGPT1, MEF2C, or ZNF667 can suppress leukocyte adhesion and serve as a gain-of-function model to validate therapeutic potential [1,3,5].
How EDITGENE Supports negative regulation of leukocyte adhesion to vascular endothelial cell Research
Researchers studying negative regulation of leukocyte adhesion to vascular endothelial cell-related genes often need to determine whether a candidate gene is causally involved in suppressing leukocyte adhesion or is merely a bystander. CRISPR-based cell models provide the gold standard for establishing causality, and EDITGENE offers a comprehensive suite of services to accelerate this research.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of leukocyte adhesion to vascular endothelial cell research.
Frequently Asked Questions About negative regulation of leukocyte adhesion to vascular endothelial cell
What is GO:1904995?
GO:1904995 is a Gene Ontology biological process term defined as any process that stops, prevents, or reduces the frequency, rate, or extent of leukocyte adhesion to vascular endothelial cell.
What genes are involved in negative regulation of leukocyte adhesion to vascular endothelial cell?
Key genes include ANGPT1, VEGFA, MEF2C, KLF2, ZNF667, CSK, and SELP, among others [1,3,4,5].
How is leukocyte adhesion negatively regulated?
Through downregulation of adhesion molecules like P-selectin and ICAM-1, inhibition of NF-kB signaling, and modulation of Src family kinases and cytoskeletal dynamics [3,4,5].
What diseases are associated with dysregulated leukocyte adhesion?
Atherosclerosis, ischemia-reperfusion injury, chronic inflammatory diseases, and cancer metastasis [1,5,6,8].
What experimental models are used to study GO:1904995?
In vitro adhesion assays, flow chamber systems, CRISPR knockout/knock-in endothelial cells, and animal models of inflammation [3,4,5].
How does MEF2C regulate leukocyte adhesion?
MEF2C suppresses endothelial inflammation by regulating NF-kB and KLF2, reducing adhesion molecule expression.
What is the role of ZNF667 in leukocyte adhesion?
ZNF667 attenuates leukocyte-endothelial adhesion via downregulation of P-selectin in skin flap following remote limb ischemic preconditioning.
How does Csk control leukocyte extravasation?
Csk locally regulates Src family kinases and cortactin signaling, affecting endothelial junctional dynamics and leukocyte transmigration.
Can CRISPR be used to study negative regulation of leukocyte adhesion?
Yes, CRISPR knockout, knock-in, and overexpression models enable causal dissection of genes involved in this process [3,4,5].
What is the clinical relevance of GO:1904995?
It is relevant for developing anti-inflammatory therapies, reducing atherosclerosis, and preventing ischemia-reperfusion injury [1,5,8].
Conclusion
GO:1904995, negative regulation of leukocyte adhesion to vascular endothelial cell, represents a critical biological brake on inflammation and vascular pathology. The integration of QuickGO definitions with published literature reveals a complex network of genes and signaling pathways, including ANGPT1, MEF2C, KLF2, ZNF667, and CSK, that suppress leukocyte adhesion. Understanding these mechanisms offers therapeutic opportunities for inflammatory diseases, atherosclerosis, and cancer. CRISPR-based cell models and screening approaches are indispensable for dissecting these pathways and identifying novel regulators.
References
- 1. Ismail H et al.. 2012. Angiopoietin-1 and vascular endothelial growth factor regulation of leukocyte adhesion to endothelial cells: role of nuclear receptor-77.. Arterioscler Thromb Vasc Biol 32(7):1707-16 PMID: 22628435
- 2. Lucke S et al.. 2010. Endothelial functions of sphingosine-1-phosphate.. Cell Physiol Biochem 26(1):87-96 PMID: 20502008
- 3. Xu Z et al.. 2015. Transcription factor MEF2C suppresses endothelial cell inflammation via regulation of NF-κB and KLF2.. J Cell Physiol 230(6):1310-20 PMID: 25474999
- 4. Stegmeyer RI et al.. 2024. Csk controls leukocyte extravasation via local regulation of Src family kinases and cortactin signaling.. Front Immunol 15:1480152 PMID: 39530094
- 5. Chen Z et al.. 2021. ZNF667 attenuates leukocyte-endothelial adhesion via downregulation of P-selectin in skin flap following remote limb ischemic preconditioning.. Cell Biol Int 45(7):1477-1486 PMID: 33710682
- 6. Lessner SM et al.. 2004. Matrix metalloproteinases and vascular endothelium-mononuclear cell close encounters.. Trends Cardiovasc Med 14(3):105-11 PMID: 15121158
- 7. Okamoto T et al.. 2014. 6-Methylsulfinylhexyl isothiocyanate modulates endothelial cell function and suppresses leukocyte adhesion.. J Nat Med 68(1):144-53 PMID: 23760613
- 8. Calvier L et al.. 2024. Safety of Anti-Reelin Therapeutic Approaches for Chronic Inflammatory Diseases.. Cells 13(7) PMID: 38607022
