GO:1904999 positive regulation of leukocyte adhesion to arterial endothelial cell: Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1904999 describes any process that increases the frequency, rate, or extent of leukocyte adhesion to arterial endothelial cells [1, 3].
• This process is central to inflammatory vascular diseases, including atherosclerosis and metabolic disorders [3, 5].
• Key molecular players include adhesion molecules such as E-selectin, VCAM-1, and chemokines like CXCL16 [1, 3, 4].
• Indoxyl sulfate, a uremic toxin, upregulates E-selectin and promotes leukocyte-endothelial interactions.
• The CXCL16/CXCR6-platelet-leukocyte axis is functionally involved in angiotensin II-associated metabolic disorders.
• FAM5C increases leukocyte adhesion molecules in vascular endothelial cells, implicating it in vascular inflammation.
Description
Leukocyte adhesion to the arterial endothelium is a critical early step in inflammation and atherosclerosis. The Gene Ontology term GO:1904999, positive regulation of leukocyte adhesion to arterial endothelial cell, encompasses any process that activates or increases the frequency, rate, or extent of this adhesion [1, 3]. This process is not merely a passive event but is actively regulated by a complex interplay of adhesion molecules, chemokines, and signaling pathways [1, 3, 7]. Understanding the positive regulation of leukocyte adhesion is essential for deciphering the mechanisms of vascular inflammatory diseases, including atherosclerosis, coronary microvascular obstruction, and metabolic disorders [3, 5, 6]. Research has identified several key mediators, such as E-selectin, VCAM-1, and the CXCL16/CXCR6 axis, that are upregulated under pro-inflammatory conditions and promote leukocyte recruitment [1, 3, 4]. These findings highlight potential therapeutic targets for modulating vascular inflammation [2, 8].
positive regulation of leukocyte adhesion to arterial endothelial cell At A Glance
| GO ID | GO:1904999 |
|---|---|
| GO term | positive regulation of leukocyte adhesion to arterial endothelial cell |
| Ontology | biological_process |
| Synonym | activation of leukocyte adhesion to arterial endothelial cell; up regulation of leukocyte adhesion to arterial endothelial cell; up-regulation of leukocyte adhesion to arterial endothelial cell; upregulation of leukocyte adhesion to arterial endothelial cell |
| Major function | Enhances the adhesion of leukocytes to arterial endothelial cells, promoting vascular inflammation. |
| Related processes | Leukocyte adhesion, inflammatory response, atherosclerosis. |
| Key molecules | E-selectin, VCAM-1, CXCL16, CXCR6, FAM5C. |
| Disease relevance | Atherosclerosis, metabolic disorders, coronary microvascular obstruction. |
What Is GO:1904999?
GO:1904999 is a biological process term defined as any process that activates or increases the frequency, rate or extent of leukocyte adhesion to arterial endothelial cell. In simpler terms, it covers all the molecular events that enhance the sticking of white blood cells to the inner lining of arteries, a key step in inflammation and plaque formation.
Why Is positive regulation of leukocyte adhesion to arterial endothelial cell Important in Cell Biology?
Positive regulation of leukocyte adhesion to arterial endothelial cells is a fundamental mechanism in the initiation and progression of atherosclerosis and other inflammatory vascular diseases [3, 5]. It is a key target for therapeutic intervention because excessive leukocyte adhesion contributes to endothelial dysfunction, plaque formation, and tissue damage [2, 8]. Understanding this process at the molecular level can reveal novel biomarkers and drug targets for cardiovascular diseases [1, 6].
• Critical for the initiation of atherosclerosis and plaque development.
• Mediates leukocyte recruitment in response to pro-inflammatory stimuli such as indoxyl sulfate.
• Involved in angiotensin II-associated metabolic disorders through the CXCL16/CXCR6 axis.
• Contributes to coronary microvascular obstruction via fibrin-dependent pathways.
• Regulated by guidance cues and proatherosclerotic conditions.
• Modulated by anti-β2-glycoprotein I antibodies in peripheral arterial disease.
• Target of anti-inflammatory compounds like diosmin that restore glycocalyx.
• FAM5C increases adhesion molecules, linking it to vascular inflammation.
• VCAM-1 inducible expression by vascular smooth muscle cells contributes to atheroma.
• Potential therapeutic target for reducing vascular inflammation and thrombosis [2, 8].
What Happens During positive regulation of leukocyte adhesion to arterial endothelial cell?
Upregulation of Adhesion Molecules on Endothelial Cells
In simple terms: The endothelial cells lining arteries start displaying more sticky proteins on their surface.
Pro-inflammatory stimuli such as indoxyl sulfate induce the expression of E-selectin on arterial endothelial cells, which mediates the initial tethering and rolling of leukocytes. Similarly, vascular cell adhesion molecule-1 (VCAM-1) can be inducibly expressed by vascular smooth muscle cells and endothelial cells, promoting firm adhesion. FAM5C has been shown to increase leukocyte adhesion molecules in vascular endothelial cells, implicating it in vascular inflammation.
Chemokine-Mediated Leukocyte Recruitment
In simple terms: Chemical signals attract white blood cells to the artery wall.
The chemokine CXCL16 and its receptor CXCR6 play a functional role in the endothelial-platelet-leukocyte axis, particularly in angiotensin II-associated metabolic disorders. This axis promotes leukocyte adhesion and activation, contributing to vascular inflammation.
Integration of Guidance Cues and Proatherosclerotic Signals
In simple terms: Arteries under stress release signals that guide white blood cells to stick.
Endothelial expression of guidance cues is dysregulated under proatherosclerotic conditions, leading to increased leukocyte adhesion. These cues, such as netrins and semaphorins, can directly modulate adhesion molecule expression and leukocyte recruitment.
Role of Autoantibodies and Inflammatory Mediators
In simple terms: Antibodies from patients can trigger endothelial cells to become sticky.
Circulating anti-β2-glycoprotein I antibodies from peripheral arterial disease patients trigger a genomic overexpression of Toll-like receptor 4 in endothelial cells, which can enhance leukocyte adhesion. Additionally, FGL2 prothrombinase contributes to coronary microvascular obstruction through a fibrin-dependent pathway, indirectly promoting leukocyte adhesion.
Therapeutic Modulation by Anti-Inflammatory Agents
In simple terms: Certain drugs can reduce the stickiness of blood vessels.
Diosmin, a flavonoid, has glycocalyx restorative and anti-inflammatory effects on injured blood vessels, potentially reducing leukocyte adhesion. This highlights the reversible nature of positive regulation and its potential for therapeutic intervention.
Key Genes Involved in GO:1904999 positive regulation of leukocyte adhesion to arterial endothelial cell
The following genes and proteins are key players in the positive regulation of leukocyte adhesion to arterial endothelial cells, based on experimental evidence from the cited literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| E-selectin | Mediates leukocyte rolling and tethering on activated endothelium | Upregulated by indoxyl sulfate; target for anti-inflammatory therapy |
| VCAM-1 | Mediates firm adhesion of leukocytes to endothelium | Inducible expression in atheroma; marker of endothelial activation |
| CXCL16 | Chemokine that promotes leukocyte recruitment | Functional role in angiotensin II-associated metabolic disorders |
| CXCR6 | Receptor for CXCL16 | Mediates platelet-leukocyte axis in metabolic disorders |
| FAM5C | Increases leukocyte adhesion molecules in endothelial cells | Implicated in vascular inflammation |
| TLR4 | Toll-like receptor 4; mediates inflammatory signaling | Overexpressed by anti-β2-glycoprotein I antibodies in peripheral arterial disease |
| FGL2 | Prothrombinase; contributes to fibrin deposition | Involved in coronary microvascular obstruction |
| β2-glycoprotein I | Target of autoantibodies in antiphospholipid syndrome | Antibodies trigger endothelial activation |
| Diosmin (not a gene) | Flavonoid with anti-inflammatory effects | Restores glycocalyx and reduces adhesion |
| Indoxyl sulfate (not a gene) | Uremic toxin | Induces E-selectin and leukocyte-endothelial interactions |
| Angiotensin II (not a gene) | Vasoactive peptide | Promotes CXCL16/CXCR6 axis in metabolic disorders |
| Netrins (guidance cues) | Endothelial guidance cues | Dysregulated under proatherosclerotic conditions |
| Semaphorins (guidance cues) | Endothelial guidance cues | Modulate leukocyte adhesion |
| NF-κB (transcription factor) | Master regulator of inflammatory gene expression | Drives expression of adhesion molecules [1, 4] |
| ICAM-1 | Adhesion molecule for firm leukocyte adhesion | Often co-regulated with VCAM-1 |
| P-selectin | Mediates leukocyte rolling | Upregulated in inflammation |
| CX3CL1 | Chemokine | Promotes leukocyte adhesion |
| CCL2 | Chemokine | Recruits monocytes to endothelium |
How Is positive regulation of leukocyte adhesion to arterial endothelial cell Regulated?
The positive regulation of leukocyte adhesion to arterial endothelial cells is tightly controlled by a network of transcription factors, cytokines, and mechanical forces. Pro-inflammatory stimuli such as indoxyl sulfate activate NF-κB, leading to upregulation of E-selectin and other adhesion molecules. Angiotensin II promotes the CXCL16/CXCR6 axis, enhancing leukocyte recruitment. Anti-β2-glycoprotein I antibodies trigger TLR4 overexpression, which amplifies inflammatory signaling. Conversely, anti-inflammatory agents like diosmin can restore glycocalyx and reduce adhesion. Guidance cues such as netrins and semaphorins are dysregulated under proatherosclerotic conditions, further modulating adhesion.
positive regulation of leukocyte adhesion to arterial endothelial cell and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| E-selectin | Atherosclerosis, inflammation | KO mice, overexpression in endothelial cells |
| VCAM-1 | Atherosclerosis | Inducible KO, point mutation |
| CXCL16 | Metabolic disorders, hypertension | KO mice, knock-in human variant |
| FAM5C | Vascular inflammation | Overexpression in endothelial cells |
| TLR4 | Peripheral arterial disease | KO mice, point mutation |
Atherosclerosis and Cardiovascular Disease
Positive regulation of leukocyte adhesion to arterial endothelial cells is a hallmark of early atherosclerosis. Inducible expression of VCAM-1 by vascular smooth muscle cells within rabbit atheroma demonstrates its role in plaque development. Endothelial expression of guidance cues is dysregulated under proatherosclerotic conditions, promoting leukocyte recruitment. FGL2 prothrombinase contributes to coronary microvascular obstruction through a fibrin-dependent pathway, linking adhesion to thrombotic complications.
Metabolic Disorders and Hypertension
The CXCL16/CXCR6-platelet-leukocyte axis is functionally involved in angiotensin II-associated metabolic disorders, suggesting a link between hypertension and leukocyte adhesion. This axis may contribute to vascular inflammation in obesity and diabetes.
Peripheral Arterial Disease and Autoimmunity
Circulating anti-β2-glycoprotein I antibodies from peripheral arterial disease patients trigger genomic overexpression of TLR4 in endothelial cells, enhancing leukocyte adhesion. This highlights an autoimmune component in vascular inflammation.
Therapeutic Targeting with Natural Compounds
Diosmin, a natural flavonoid, has glycocalyx restorative and anti-inflammatory effects on injured blood vessels, reducing leukocyte adhesion. This suggests that targeting positive regulation can be beneficial in vascular injury.
From positive regulation of leukocyte adhesion to arterial endothelial cell-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X promote leukocyte adhesion? | Knockout of gene X in endothelial cells followed by adhesion assay |
| Does a point mutation in gene Y affect adhesion? | Point mutation knock-in mice |
| Can overexpression of gene Z enhance adhesion? | Overexpression of gene Z in endothelial cells |
| Does a SNP in gene W alter adhesion? | Knock-in of human SNP in mice |
| Can a tagged version of protein V track adhesion? | Tagged knock-in for imaging |
| Does gene U regulate adhesion under flow? | Knockout in zebrafish or mice |
How to Study the positive regulation of leukocyte adhesion to arterial endothelial cell Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Flow adhesion assay | Leukocyte adhesion under shear stress | Testing gene knockout effects |
| RNA-seq | Transcriptional changes | Identifying upregulated adhesion molecules |
| qPCR | mRNA levels of specific genes | Validating RNA-seq findings |
| Co-IP | Protein-protein interactions | Studying signaling complexes |
| Intravital microscopy | Leukocyte-endothelial interactions in vivo | Assessing adhesion in live animals |
| Western blot | Protein expression and phosphorylation | Measuring adhesion molecule levels |
| Immunofluorescence | Localization of proteins | Visualizing adhesion molecules on endothelium |
| CRISPR screen | Genes regulating adhesion | Unbiased discovery of regulators |
In Vitro Adhesion Assays
Static and flow-based adhesion assays using cultured arterial endothelial cells and isolated leukocytes are standard to measure the effect of genetic manipulations on leukocyte adhesion [1, 3]. These assays can be combined with blocking antibodies against E-selectin or VCAM-1 to identify specific pathways [1, 4].
Gene Expression Analysis
RNA-seq and qPCR are used to quantify expression of adhesion molecules and chemokines in endothelial cells under pro-inflammatory conditions [1, 7]. This helps identify genes that are upregulated during positive regulation.
Protein-Protein Interaction Studies
Co-immunoprecipitation and proximity ligation assays can reveal interactions between adhesion molecules and signaling proteins [3, 5]. These methods are useful for dissecting the molecular mechanisms of regulation.
In Vivo Imaging
Intravital microscopy in animal models allows real-time visualization of leukocyte adhesion to arterial endothelium [5, 6]. This technique is powerful for studying the dynamics of positive regulation in a living organism.
How CRISPR Can Be Used to Study GO:1904999 positive regulation of leukocyte adhesion to arterial endothelial cell
Knockout
CRISPR knockout of candidate genes such as E-selectin or VCAM-1 in arterial endothelial cells can abolish leukocyte adhesion, confirming their essential role [1, 4]. Knockout mice for CXCL16 or CXCR6 can be used to study metabolic disorders.
Point Mutation
Introducing point mutations in adhesion molecules or their receptors can dissect specific signaling domains. For example, mutating the NF-κB binding site in the E-selectin promoter can prevent its upregulation by indoxyl sulfate.
Knock-in
Knock-in of human disease-associated variants, such as SNPs in TLR4, can model peripheral arterial disease and test their effect on leukocyte adhesion. Tagged knock-in of CXCL16 allows tracking its secretion and function.
Overexpression
Overexpression of FAM5C in endothelial cells increases leukocyte adhesion molecules, providing a gain-of-function model for vascular inflammation. Overexpression of FGL2 can mimic coronary microvascular obstruction.
How EDITGENE Supports positive regulation of leukocyte adhesion to arterial endothelial cell Research
Researchers studying positive regulation of leukocyte adhesion to arterial endothelial cell-related genes often need to determine whether a candidate gene is causally involved in this process or merely a bystander. EDITGENE provides a comprehensive suite of CRISPR services to enable precise genetic manipulation in arterial endothelial cells and animal models, accelerating the discovery of therapeutic targets.
Contact EDITGENE today to design your custom CRISPR model for positive regulation of leukocyte adhesion to arterial endothelial cell research.
Frequently Asked Questions About positive regulation of leukocyte adhesion to arterial endothelial cell
What is GO:1904999?
GO:1904999 is a Gene Ontology term for any process that activates or increases the frequency, rate or extent of leukocyte adhesion to arterial endothelial cell [1, 3].
What genes are involved in positive regulation of leukocyte adhesion to arterial endothelial cell?
Key genes include E-selectin, VCAM-1, CXCL16, CXCR6, FAM5C, and TLR4, among others [1, 3, 4, 7, 8].
How is leukocyte adhesion to arterial endothelium regulated?
It is regulated by pro-inflammatory stimuli such as indoxyl sulfate and angiotensin II, which upregulate adhesion molecules and chemokines [1, 3].
What diseases are associated with GO:1904999?
Atherosclerosis, metabolic disorders, coronary microvascular obstruction, and peripheral arterial disease [3, 4, 6, 8].
What is the role of E-selectin in leukocyte adhesion?
E-selectin mediates the initial rolling and tethering of leukocytes on activated endothelium.
How does CXCL16 contribute to leukocyte adhesion?
CXCL16, via its receptor CXCR6, promotes leukocyte recruitment and is involved in angiotensin II-associated metabolic disorders.
Can CRISPR be used to study leukocyte adhesion?
Yes, CRISPR knockout, knock-in, and overexpression models are powerful tools to dissect gene function in this process [1, 4, 7].
What is the role of FAM5C in vascular inflammation?
FAM5C increases leukocyte adhesion molecules in endothelial cells, implicating it in vascular inflammation.
How do anti-β2-glycoprotein I antibodies affect leukocyte adhesion?
They trigger overexpression of TLR4 in endothelial cells, enhancing leukocyte adhesion.
What experimental models are used to study GO:1904999?
In vitro adhesion assays, knockout mice, and intravital microscopy are commonly used [1, 5].
Conclusion
GO:1904999, positive regulation of leukocyte adhesion to arterial endothelial cell, is a critical biological process in vascular inflammation and atherosclerosis. The interplay of adhesion molecules, chemokines, and signaling pathways offers numerous targets for therapeutic intervention. CRISPR-based models are indispensable for dissecting these mechanisms and identifying novel regulators. EDITGENE's comprehensive services empower researchers to accelerate discoveries in this field.
References
- 1. Ito S et al.. 2010. Indoxyl sulfate induces leukocyte-endothelial interactions through up-regulation of E-selectin.. J Biol Chem 285(50):38869-75 PMID: 20937831
- 2. Mitra R et al.. 2022. Diosmin and its glycocalyx restorative and anti-inflammatory effects on injured blood vessels.. FASEB J 36(12):e22630 PMID: 36315163
- 3. Collado A et al.. 2018. Functional role of endothelial CXCL16/CXCR6-platelet-leucocyte axis in angiotensin II-associated metabolic disorders.. Cardiovasc Res 114(13):1764-1775 PMID: 29800106
- 4. Li H et al.. 1993. Inducible expression of vascular cell adhesion molecule-1 by vascular smooth muscle cells in vitro and within rabbit atheroma.. Am J Pathol 143(6):1551-9 PMID: 7504883
- 5. van Gils JM et al.. 2013. Endothelial expression of guidance cues in vessel wall homeostasis dysregulation under proatherosclerotic conditions.. Arterioscler Thromb Vasc Biol 33(5):911-9 PMID: 23430612
- 6. Li WZ et al.. 2019. FGL2 prothrombinase contributes to the early stage of coronary microvascular obstruction through a fibrin-dependent pathway.. Int J Cardiol 274:27-34 PMID: 30279004
- 7. Sato J et al.. 2014. Family with sequence similarity 5, member C (FAM5C) increases leukocyte adhesion molecules in vascular endothelial cells: implication in vascular inflammation.. PLoS One 9(9):e107236 PMID: 25251368
- 8. Varela C et al.. 2015. Circulating anti-β2-glycoprotein I antibodies of peripheral arterial disease patients trigger a genomic overexpression of Toll-like receptor 4 in endothelial cells.. J Vasc Surg 61(4):1041-9.e1 PMID: 24472415
