GO:1904905 negative regulation of endothelial cell-matrix adhesion: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1904905 describes any process that stops, prevents, or reduces the frequency, rate, or extent of endothelial cell-matrix adhesion.
• Endothelial cell-matrix adhesion is dynamically regulated by integrin-linked kinase (ILK), Rac-1, and focal adhesion turnover machinery.
• Negative regulation of this process is critical for limiting vascular permeability, controlling angiogenesis, and preventing pathological cell invasion.
• Key molecular players include ILK, Rac-1, DLC1, JAM-C, PECAM-1, and semaphorins, which modulate integrin adhesion at the endothelial interface.
• Dysregulation of endothelial cell-matrix adhesion contributes to cancer metastasis, inflammation, and vascular disease.
• CRISPR knockout, point mutation, and knock-in models enable precise dissection of genes controlling endothelial adhesion.
Description
Endothelial cells line the inner surface of blood vessels and must tightly regulate their adhesion to the surrounding extracellular matrix (ECM) to maintain vascular barrier function, control angiogenesis, and respond to mechanical forces. The Gene Ontology term GO:1904905, negative regulation of endothelial cell-matrix adhesion, captures the biological processes that actively reduce or prevent the attachment of endothelial cells to ECM components. This regulation is essential for normal vascular homeostasis and is frequently subverted in disease states such as cancer, inflammation, and edema. Understanding the molecular mechanisms that negatively regulate endothelial cell-matrix adhesion is therefore a major research focus. Integrin-linked kinase (ILK) and Rac-1 have been shown to control cell-matrix adhesion dynamics, providing a paradigm for how intracellular signaling modulates adhesion turnover. Similarly, DLC1 promotes mechanotransductive feedback for YAP via RhoGAP-mediated focal adhesion turnover, directly influencing endothelial adhesion stability. Junctional adhesion molecule C (JAM-C) limits glioblastoma stem-like cell invasion by regulating integrin adhesion at the endothelial interface, illustrating how negative regulation of adhesion can restrict pathological cell migration. This article synthesizes authoritative GO annotations and verified PubMed literature to provide a research-grade overview of GO:1904905, its molecular players, disease relevance, and experimental approaches for studying it.
negative regulation of endothelial cell-matrix adhesion At A Glance
| GO ID | GO:1904905 |
|---|---|
| GO term | negative regulation of endothelial cell-matrix adhesion |
| Ontology | biological_process |
| Synonym | down regulation of endothelial cell-matrix adhesion; down-regulation of endothelial cell-matrix adhesion; downregulation of endothelial cell-matrix adhesion; inhibition of endothelial cell-matrix adhesion |
| Major function | Actively reduces or prevents endothelial cell attachment to extracellular matrix components |
| Related cellular process | Regulation of cell-matrix adhesion, focal adhesion turnover, vascular permeability |
| Key molecular players | Integrins, ILK, Rac-1, DLC1, JAM-C, PECAM-1, semaphorins |
| Disease relevance | Cancer metastasis, inflammation, vascular permeability disorders |
What Is GO:1904905?
GO:1904905 is defined as any process that stops, prevents, or reduces the frequency, rate, or extent of endothelial cell-matrix adhesion. In practical terms, it encompasses signaling events, protein-protein interactions, and cytoskeletal rearrangements that weaken or dissolve the physical connections between endothelial cells and ECM proteins such as fibronectin, collagen, and laminin. This negative regulation is not simply a passive loss of adhesion but an active, signal-driven process that can be triggered by mechanical cues, soluble factors, or cell-cell contact.
Why Is negative regulation of endothelial cell-matrix adhesion Important in Cell Biology?
Negative regulation of endothelial cell-matrix adhesion is fundamental to vascular biology because it allows endothelial cells to dynamically remodel their attachments during angiogenesis, wound healing, and immune cell trafficking. When this process is impaired, endothelial cells may become hyper-adhesive, leading to increased vascular permeability, edema, and aberrant angiogenesis. Conversely, excessive negative regulation can promote cell detachment and metastasis in cancer. Understanding the molecular switches that control this balance is therefore critical for developing therapies that target vascular leak, tumor invasion, and inflammatory diseases.
• Controls vascular permeability and barrier function in health and disease.
• Regulates angiogenesis by allowing endothelial cells to detach and migrate during new vessel formation.
• Limits pathological cell invasion, as shown for JAM-C in glioblastoma stem-like cells.
• Modulates mechanotransduction through focal adhesion turnover and YAP signaling.
• Involves integrin-linked kinase and Rac-1 in adhesion dynamics.
• PECAM-1 acts as a negative regulator of platelet-collagen interactions, highlighting related adhesion control mechanisms.
• Dysregulation contributes to cancer metastasis and inflammation.
• Provides targets for anti-angiogenic and anti-metastatic therapies.
• Relevant to wound healing through keratinocyte-fibroblast interactions.
• Involved in airway inflammation and neutrophil transepithelial migration via DEL-1.
What Happens During negative regulation of endothelial cell-matrix adhesion?
Initiation by Mechanical or Soluble Cues
In simple terms: The process starts when endothelial cells receive signals from their environment, such as blood flow or chemical messengers.
Negative regulation of endothelial cell-matrix adhesion can be initiated by mechanical forces (shear stress) or soluble factors that activate intracellular signaling. DLC1 promotes mechanotransductive feedback for YAP via RhoGAP-mediated focal adhesion turnover, directly linking mechanical cues to adhesion disassembly. Similarly, semaphorins regulate vascular morphogenesis by modulating integrin-mediated adhesion.
Integrin Inactivation and Focal Adhesion Turnover
In simple terms: The cell actively dismantles the protein clusters that glue it to the matrix.
Integrins are the primary receptors for ECM proteins. Negative regulation involves conformational changes or clustering disruption of integrins, leading to focal adhesion turnover. ILK and Rac-1 regulate cell-matrix adhesion dynamics, with ILK acting as a key node in this process. DLC1's RhoGAP activity further promotes focal adhesion turnover by inactivating Rho GTPases.
Cytoskeletal Rearrangement and Cell Detachment
In simple terms: The cell's internal skeleton pulls away from the matrix attachment points.
Actin cytoskeleton remodeling is essential for reducing adhesion. Rac-1, a Rho family GTPase, controls actin dynamics downstream of ILK to modulate adhesion strength. JAM-C regulates integrin adhesion at the endothelial interface, limiting glioblastoma stem-like cell invasion, which requires cytoskeletal changes.
Modulation by Cell-Cell Contact and Junctional Molecules
In simple terms: Contacts with neighboring cells can signal the cell to loosen its grip on the matrix.
Junctional adhesion molecules such as JAM-C and PECAM-1 influence cell-matrix adhesion. PECAM-1 is a negative regulator of platelet-collagen interactions, demonstrating how junctional proteins can suppress adhesive events. JAM-C limits invasion by regulating integrin adhesion at the endothelial interface.
Feedback and Resolution
In simple terms: The process is self-limiting, with feedback loops that restore adhesion when needed.
Negative regulation is balanced by positive signals to avoid uncontrolled detachment. DLC1-mediated YAP feedback provides one such loop, where focal adhesion turnover influences transcriptional programs. DEL-1 inhibits airway neutrophilic inflammation, partly by modulating adhesion molecules, illustrating cross-talk between adhesion and inflammation.
Key Genes Involved in GO:1904905 negative regulation of endothelial cell-matrix adhesion
The following genes and proteins have been experimentally linked to the regulation of endothelial cell-matrix adhesion and its negative control.
| Gene | Major Role | Research Relevance |
|---|---|---|
| ILK | Regulates cell-matrix adhesion dynamics and Rac-1 activity | Key kinase in adhesion turnover; target for adhesion studies |
| Rac-1 | GTPase controlling actin cytoskeleton and adhesion dynamics | Downstream effector of ILK in adhesion regulation |
| DLC1 | RhoGAP promoting focal adhesion turnover and YAP feedback | Mechanotransduction and adhesion disassembly |
| JAM-C | Junctional adhesion molecule limiting integrin adhesion at endothelial interface | Regulates glioblastoma stem-like cell invasion |
| PECAM-1 | Negative regulator of platelet-collagen interactions | Model for inhibitory adhesion signaling |
| Semaphorins | Regulate vascular morphogenesis via integrin adhesion | Angiogenesis and endothelial adhesion |
| DEL-1 | Anti-neutrophil transepithelial migration molecule | Inhibits airway neutrophilic inflammation |
| Integrins | Primary ECM receptors | Central to cell-matrix adhesion |
| YAP | Transcriptional co-activator in mechanotransduction | Downstream of DLC1-mediated focal adhesion turnover |
| Rho GTPases | Regulate cytoskeletal dynamics | Targets of DLC1 RhoGAP activity |
| Keratinocyte autophagy proteins | Facilitate wound healing via fibroblast activation | Indirect link to adhesion remodeling |
| Fibroblasts | ECM-producing cells in wound healing | Interact with keratinocytes during healing |
| Endothelial cells | Vascular lining cells | Primary cells for adhesion studies |
| Neutrophils | Immune cells undergoing transepithelial migration | Regulated by DEL-1 |
| Glioblastoma stem-like cells | Invasive cancer cells | Invasion limited by JAM-C |
| Platelets | Blood cells interacting with collagen | PECAM-1 negatively regulates this interaction |
How Is negative regulation of endothelial cell-matrix adhesion Regulated?
The negative regulation of endothelial cell-matrix adhesion is itself controlled by multiple signaling pathways. ILK and Rac-1 form a regulatory axis where ILK modulates Rac-1 activity to control adhesion dynamics. DLC1 provides a mechanotransductive feedback loop involving RhoGAP activity and YAP, linking adhesion turnover to transcriptional outputs. Junctional molecules like JAM-C and PECAM-1 can inhibit adhesive events through homophilic or heterophilic interactions. Additionally, inflammatory mediators such as DEL-1 can suppress neutrophil transepithelial migration, indirectly affecting endothelial adhesion. These regulatory layers ensure that endothelial adhesion is dynamically tuned to physiological demands.
negative regulation of endothelial cell-matrix adhesion and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| JAM-C | Glioblastoma invasion | Knockout in glioblastoma stem-like cells |
| DLC1 | Cancer mechanotransduction | Point mutation in DLC1 RhoGAP domain |
| ILK | Vascular permeability | Endothelial-specific knockout |
| PECAM-1 | Thrombosis and inflammation | Knockout mice |
| DEL-1 | Asthma and airway inflammation | Overexpression in airway epithelium |
Cancer Metastasis and Invasion
Negative regulation of endothelial cell-matrix adhesion can limit the invasion of cancer cells. JAM-C restricts glioblastoma stem-like cell invasion by regulating integrin adhesion at the endothelial interface, suggesting that loss of this negative regulation promotes metastasis. Similarly, DLC1-mediated focal adhesion turnover influences YAP activity, which is linked to cancer progression.
Vascular Permeability and Inflammation
Increased endothelial permeability is a hallmark of inflammation and edema. Mechanisms of increased endothelial permeability involve disruption of cell-matrix and cell-cell adhesions. DEL-1 inhibits airway neutrophilic inflammation, partly by modulating adhesion molecules, highlighting the therapeutic potential of targeting negative regulation.
Angiogenesis and Vascular Morphogenesis
Semaphorins regulate vascular morphogenesis by controlling integrin-mediated adhesion, and negative regulation of endothelial cell-matrix adhesion is essential for sprouting angiogenesis. Dysregulated angiogenesis contributes to tumor growth and retinopathies.
Wound Healing
Keratinocyte autophagy enables the activation of keratinocytes and fibroblasts and facilitates wound healing, a process that requires dynamic adhesion remodeling. Negative regulation of endothelial cell-matrix adhesion may influence vascularization during wound repair.
From negative regulation of endothelial cell-matrix adhesion-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does ILK negatively regulate endothelial adhesion? | ILK knockout endothelial cells |
| How does DLC1 RhoGAP activity affect focal adhesion turnover? | DLC1 point mutation knock-in |
| Can JAM-C limit glioblastoma invasion? | JAM-C overexpression in stem-like cells |
| What is the role of PECAM-1 in platelet-collagen adhesion? | PECAM-1 knockout platelets |
| Does DEL-1 inhibit neutrophil migration? | DEL-1 overexpression in airway models |
| How does autophagy in keratinocytes affect wound healing? | Keratinocyte-specific autophagy knockout |
How to Study the negative regulation of endothelial cell-matrix adhesion Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Live-cell imaging | Focal adhesion dynamics | Real-time adhesion turnover |
| Rho GTPase pull-down | Rac-1/RhoA activity | Signaling downstream of ILK |
| CRISPR knockout screen | Gene essentiality for adhesion | Discovery of negative regulators |
| Proteomics | Focal adhesion composition | Identifying novel components |
| Permeability assays | Endothelial barrier function | Testing negative regulation |
| Transwell invasion | Cell invasion through matrix | JAM-C effects on glioblastoma |
| Immunofluorescence | Protein localization | JAM-C and integrin co-localization |
| Wound healing assay | Cell migration | Keratinocyte-fibroblast interactions |
Live-Cell Imaging of Adhesion Dynamics
Fluorescence microscopy of GFP-tagged focal adhesion proteins (e.g., paxillin, vinculin) allows real-time visualization of adhesion turnover. This method has been used to study ILK and Rac-1 effects on cell-matrix adhesion.
Rho GTPase Activity Assays
Pull-down assays or FRET biosensors measure Rac-1 and RhoA activity, which are critical for adhesion regulation. DLC1 RhoGAP activity can be assessed by monitoring RhoA-GTP levels.
CRISPR Screening for Adhesion Regulators
Genome-wide CRISPR knockout screens can identify genes whose loss alters endothelial cell adhesion to ECM. This approach is powerful for discovering novel negative regulators.
Proteomics of Focal Adhesions
Mass spectrometry-based proteomics of isolated focal adhesions reveals changes in protein composition upon negative regulation. This can identify signaling nodes like ILK and DLC1.
How CRISPR Can Be Used to Study GO:1904905 negative regulation of endothelial cell-matrix adhesion
Knockout
CRISPR knockout of genes such as ILK, DLC1, or JAM-C in endothelial cells can reveal their role in negative regulation of cell-matrix adhesion. For example, ILK knockout would be expected to impair adhesion turnover.
Point Mutation
Introducing point mutations in the RhoGAP domain of DLC1 can dissect its catalytic contribution to focal adhesion turnover without affecting protein stability.
Knock-in
Knock-in of fluorescent tags (e.g., GFP) at endogenous loci allows real-time tracking of proteins like JAM-C or PECAM-1 during adhesion regulation.
Overexpression
Overexpression of DEL-1 or JAM-C can test whether increasing their levels enhances negative regulation of adhesion and limits inflammation or invasion.
How EDITGENE Supports negative regulation of endothelial cell-matrix adhesion Research
Researchers studying negative regulation of endothelial cell-matrix adhesion-related genes often need to determine whether a candidate gene is causally involved in adhesion control or merely correlated with it. EDITGENE provides a comprehensive suite of CRISPR-based services to enable such causal studies.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of endothelial cell-matrix adhesion research.
Frequently Asked Questions About negative regulation of endothelial cell-matrix adhesion
What is GO:1904905?
GO:1904905 is the Gene Ontology term for negative regulation of endothelial cell-matrix adhesion, defined as any process that stops, prevents, or reduces the frequency, rate, or extent of endothelial cell-matrix adhesion.
What genes are involved in negative regulation of endothelial cell-matrix adhesion?
Key genes include ILK, Rac-1, DLC1, JAM-C, PECAM-1, semaphorins, and DEL-1, as shown in studies of adhesion dynamics and vascular biology.
How does ILK regulate endothelial cell-matrix adhesion?
ILK regulates cell-matrix adhesion dynamics and Rac-1 activity, influencing focal adhesion turnover.
What is the role of DLC1 in endothelial adhesion?
DLC1 promotes mechanotransductive feedback for YAP via RhoGAP-mediated focal adhesion turnover, thereby negatively regulating adhesion.
How does JAM-C affect glioblastoma invasion?
JAM-C limits glioblastoma stem-like cell invasion by regulating integrin adhesion at the endothelial interface.
What diseases are linked to dysregulated endothelial cell-matrix adhesion?
Cancer metastasis, inflammation, vascular permeability disorders, and angiogenesis-related diseases are linked to dysregulation of this process.
What experimental models are used to study negative regulation of endothelial cell-matrix adhesion?
CRISPR knockout, point mutation, knock-in, and overexpression models in endothelial cells are commonly used.
How can I study negative regulation of endothelial cell-matrix adhesion using CRISPR?
You can use CRISPR to knock out candidate genes, introduce point mutations, or knock in tags, then assess adhesion dynamics via imaging or functional assays.
What is the role of PECAM-1 in adhesion?
PECAM-1 is a negative regulator of platelet-collagen interactions, serving as a model for inhibitory adhesion signaling.
How does DEL-1 affect inflammation?
DEL-1 inhibits airway neutrophilic inflammation by modulating adhesion molecules, indirectly affecting endothelial adhesion.
Conclusion
GO:1904905, negative regulation of endothelial cell-matrix adhesion, is a critical biological process that maintains vascular homeostasis and prevents pathological adhesion. Key molecular players such as ILK, Rac-1, DLC1, JAM-C, and PECAM-1 orchestrate this regulation through integrin inactivation, focal adhesion turnover, and cytoskeletal remodeling. Dysregulation of this process contributes to cancer, inflammation, and vascular disease, making it an attractive therapeutic target. Advanced CRISPR models and bioinformatics tools now enable precise dissection of these mechanisms, offering new opportunities for drug discovery and disease intervention.
References
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