GO:1904753 negative regulation of vascular associated smooth muscle cell migration: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1904753 describes any biological process that stops, prevents, or reduces the frequency, rate, or extent of vascular associated smooth muscle cell migration.
• Vascular smooth muscle cell (VSMC) migration is a hallmark of neointimal hyperplasia, atherosclerosis, and restenosis, making its negative regulation a key therapeutic target.
• Blood shear stress is a potent physiological negative regulator of VSMC migration, acting through endothelial-derived signals and direct mechanotransduction.
• Members of the low-density lipoprotein receptor family, including LRP1 and VLDLR, modulate VSMC migration and can suppress the migratory phenotype.
• Loss of KCNMB1 (BK channel beta-1 subunit) triggers VSMC phenotypic switching and apoptosis, indirectly linking ion channel function to migratory control.
• Sclerostin, a Wnt signaling antagonist, influences vascular pathophysiology and may affect VSMC behavior, including migration.
• TWIST1 domains regulate smooth muscle cell phenotype, providing a transcriptional mechanism that can impinge on negative regulation of migration.
• HIX003209 promotes VSMC migration and proliferation by modulating miR-6089, illustrating how lncRNAs can oppose negative regulatory pathways.
Description
The migration of vascular associated smooth muscle cells (VSMCs) from the media to the intima is a critical event in the pathogenesis of atherosclerosis, restenosis after angioplasty, and hypertension-induced vascular remodeling. Under normal physiological conditions, VSMC migration is tightly suppressed by a variety of negative regulatory mechanisms that maintain the quiescent, contractile phenotype of these cells. The Gene Ontology term GO:1904753, negative regulation of vascular associated smooth muscle cell migration, captures the set of biological processes that stop, prevent, or reduce the frequency, rate, or extent of VSMC migration. Understanding these processes is essential for developing therapies that stabilize atherosclerotic plaques and prevent restenosis. Research into GO:1904753 has revealed that negative regulation of VSMC migration is mediated by diverse factors, including hemodynamic forces such as blood shear stress, lipoprotein receptor family members, ion channel subunits, and transcriptional regulators. For example, physiological levels of laminar shear stress actively suppress VSMC migration through endothelial-dependent and independent pathways. Similarly, LRP1 and other LDL receptor family proteins can inhibit VSMC migration by modulating extracellular matrix interactions and intracellular signaling. Disruption of these negative regulatory pathways, as seen with KCNMB1 downregulation, leads to a phenotypic switch toward a synthetic, migratory state. Given the clinical importance of VSMC migration in cardiovascular disease, the negative regulation of this process (GO:1904753) represents a promising area for therapeutic intervention. This article synthesizes current knowledge on the mechanisms, key genes, and experimental models used to study GO:1904753, with a focus on how CRISPR-based gene editing can accelerate discoveries in this field.
negative regulation of vascular associated smooth muscle cell migration At A Glance
| GO ID | GO:1904753 |
|---|---|
| GO term | negative regulation of vascular associated smooth muscle cell migration |
| Ontology | biological_process |
| Synonym | down regulation of vascular associated smooth muscle cell migration; down-regulation of vascular associated smooth muscle cell migration; downregulation of vascular associated smooth muscle cell migration; down regulation of vascular smooth muscle cell migration; down-regulation of vascular smooth muscle cell migration; downregulation of vascular smooth muscle cell migration; inhibition of vascular associated smooth muscle cell migration; inhibition of vascular smooth muscle cell migration; negative regulation of vascular smooth muscle cell migration |
| Major function | Suppression of vascular smooth muscle cell migration, preventing neointimal hyperplasia and maintaining vascular quiescence. |
| Physiological inducers | Blood shear stress, laminar flow, extracellular matrix components, and soluble factors such as sclerostin. |
| Key molecular players | LRP1, VLDLR, KCNMB1, TWIST1, and non-coding RNAs such as HIX003209/miR-6089. |
| Associated diseases | Atherosclerosis, restenosis, hypertension, and vascular remodeling. |
| Research methods | CRISPR knockout/knock-in, shear stress models, migration assays, RNA-seq, and proteomics. |
What Is GO:1904753?
GO:1904753, negative regulation of vascular associated smooth muscle cell migration, is defined as any process that stops, prevents, or reduces the frequency, rate, or extent of vascular associated smooth muscle cell migration. In simpler terms, it encompasses all biological signals and mechanisms that put the brakes on the movement of smooth muscle cells within blood vessels. This regulation is crucial for maintaining vascular homeostasis and preventing pathological conditions such as atherosclerosis and restenosis.
Why Is negative regulation of vascular associated smooth muscle cell migration Important in Cell Biology?
GO:1904753 is critically important because dysregulated VSMC migration is a central driver of cardiovascular diseases, including atherosclerosis, post-angioplasty restenosis, and hypertensive vascular remodeling. The ability to therapeutically enhance negative regulation of VSMC migration could prevent or slow these pathologies. Moreover, understanding the molecular mechanisms of GO:1904753 provides insights into fundamental vascular biology, such as how hemodynamic forces and lipoprotein receptors maintain vessel wall homeostasis. As the global burden of cardiovascular disease rises, targeting the negative regulation of VSMC migration represents a promising strategy for novel interventions.
• Prevents neointimal hyperplasia and restenosis after vascular injury.
• Maintains the contractile, quiescent phenotype of VSMCs in healthy vessels.
• Blood shear stress is a potent physiological negative regulator, linking hemodynamics to vascular health.
• Dysregulation of negative regulators such as LRP1 contributes to atherosclerosis progression.
• Loss of KCNMB1, a negative regulator of VSMC phenotypic switching, is associated with vascular dysfunction.
• Sclerostin, a Wnt antagonist, influences vascular pathophysiology and may modulate VSMC migration.
• TWIST1 transcriptional activity can suppress smooth muscle cell migration, offering a target for intervention.
• Non-coding RNAs such as HIX003209 can override negative regulation, promoting migration.
• CRISPR screens can identify novel negative regulators of VSMC migration for therapeutic development.
• Animal models of restenosis and atherosclerosis are essential for validating targets in GO:1904753.
What Happens During negative regulation of vascular associated smooth muscle cell migration?
Initiation by Hemodynamic Forces
In simple terms: Blood flow creates a force that tells smooth muscle cells to stay put.
Laminar blood shear stress is a primary physiological initiator of negative regulation of VSMC migration. Endothelial cells sense shear stress and release paracrine factors that suppress VSMC migration, while direct mechanotransduction in VSMCs can also inhibit their migratory machinery. This process involves integrin-mediated signaling and cytoskeletal reorganization that favors a stationary, contractile phenotype.
Receptor-Mediated Suppression
In simple terms: Certain receptors on the cell surface act like brakes on cell movement.
Members of the low-density lipoprotein receptor family, such as LRP1 and VLDLR, bind to extracellular ligands and initiate intracellular signals that inhibit VSMC migration. These receptors modulate actin dynamics and focal adhesion turnover, effectively reducing the cell's ability to move. Loss of these receptors correlates with increased migratory capacity in vascular disease models.
Ion Channel and Phenotypic Control
In simple terms: Ion channels help keep smooth muscle cells in a non-migratory state.
The BK channel beta-1 subunit, encoded by KCNMB1, is critical for maintaining VSMC quiescence. Reduced KCNMB1 expression leads to a phenotypic switch toward a synthetic, migratory state and increased apoptosis. Thus, KCNMB1 activity is part of the negative regulatory network that prevents excessive VSMC migration.
Transcriptional and Non-Coding RNA Regulation
In simple terms: Master switches inside the cell can turn off migration genes.
Transcription factors such as TWIST1 regulate smooth muscle cell phenotype, and specific domains of TWIST1 are required for suppressing migratory gene programs. Additionally, long non-coding RNAs like HIX003209 can promote migration by sponging microRNAs such as miR-6089, thereby relieving negative regulation. The balance between pro-migratory and anti-migratory transcripts determines the net migratory response.
Extracellular Matrix and Soluble Mediators
In simple terms: The environment around the cell can send stop signals.
Sclerostin, a secreted Wnt signaling antagonist, is emerging as a modulator of vascular pathophysiology and may influence VSMC migration. Components of the extracellular matrix, such as collagen and elastin, can also provide inhibitory cues that limit VSMC migration under normal conditions. Disruption of these environmental stop signals contributes to pathological migration.
Key Genes Involved in GO:1904753 negative regulation of vascular associated smooth muscle cell migration
The following genes and proteins have been experimentally linked to the negative regulation of vascular associated smooth muscle cell migration (GO:1904753) or to opposing pro-migratory pathways, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| LRP1 | LDL receptor family member; inhibits VSMC migration via extracellular matrix and signaling modulation | Target for enhancing negative regulation in atherosclerosis |
| VLDLR | LDL receptor family member; modulates VSMC migration | Potential therapeutic target for restenosis |
| KCNMB1 | BK channel beta-1 subunit; maintains VSMC quiescence; loss leads to phenotypic switch | Biomarker and target for vascular dysfunction |
| TWIST1 | Transcription factor; domains regulate smooth muscle cell phenotype and suppress migration | Transcriptional regulator for gene editing studies |
| HIX003209 | Long non-coding RNA; promotes VSMC migration by sponging miR-6089 | Epigenetic target to restore negative regulation |
| miR-6089 | MicroRNA; negatively regulated by HIX003209; suppresses migration | Therapeutic microRNA mimic |
| SOST | Encodes sclerostin; Wnt antagonist; influences vascular pathophysiology | Link between bone and vascular biology |
| NOTCH1 | Notch signaling component; context-dependent effects on VSMC migration | Pathway crosstalk with shear stress |
| NOTCH3 | Notch receptor; regulates VSMC phenotype and migration | Target for vascular remodeling |
| PDGFRB | Platelet-derived growth factor receptor; pro-migratory, opposes negative regulation | Kinase inhibitor target |
| MMP2 | Matrix metalloproteinase; promotes migration by degrading matrix | Enzyme target to inhibit migration |
| MMP9 | Matrix metalloproteinase; promotes VSMC migration | Biomarker of vascular remodeling |
| TGFB1 | Transforming growth factor beta; context-dependent, can inhibit migration | Cytokine target for modulating phenotype |
| MYOCD | Myocardin; master regulator of contractile VSMC phenotype | Transcriptional coactivator for quiescence |
| SRF | Serum response factor; cooperates with myocardin to maintain contractile genes | Transcription factor target |
| KLF4 | Kruppel-like factor 4; promotes phenotypic switching and migration | Repressor of contractile genes |
| ELN | Elastin; extracellular matrix component that inhibits VSMC migration | Matrix target for biomaterials |
| COL1A1 | Collagen type I; provides inhibitory matrix cues | Matrix remodeling studies |
How Is negative regulation of vascular associated smooth muscle cell migration Regulated?
The negative regulation of VSMC migration (GO:1904753) is itself subject to multiple layers of regulation. Hemodynamic shear stress is a master physiological regulator, activating endothelial nitric oxide synthase (eNOS) and other pathways that suppress VSMC migration. The low-density lipoprotein receptor family members, such as LRP1, are regulated by cholesterol levels and inflammatory cytokines, which can impair their inhibitory function. Ion channel activity, particularly BK channels containing KCNMB1, is modulated by intracellular calcium and membrane potential, and loss of KCNMB1 relieves the negative regulation. Transcriptional regulators like TWIST1 and KLF4 integrate developmental and pathological signals to control the migratory gene program. Additionally, non-coding RNAs such as HIX003209 and miR-6089 form a regulatory circuit that can override negative regulation. Sclerostin, a Wnt antagonist, is regulated by mechanical loading and hormonal factors, and its effects on vascular cells are an active area of research.
negative regulation of vascular associated smooth muscle cell migration and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| LRP1 | Atherosclerosis, restenosis | ApoE-/- or Ldlr-/- mice with LRP1 knockout in VSMCs |
| KCNMB1 | Hypertension, vascular dysfunction | KCNMB1 knockout mice or VSMC-specific knockout |
| TWIST1 | Vascular remodeling, smooth muscle phenotype | Twist1 conditional knockout mice |
| HIX003209/miR-6089 | Atherosclerosis, VSMC migration | LncRNA knockout or miR-6089 mimic in rat VSMCs |
| SOST | Vascular calcification, chronic kidney disease | Sost knockout mice or sclerostin infusion models |
Atherosclerosis and Restenosis
Atherosclerosis is characterized by the accumulation of VSMCs in the intima, where they contribute to plaque formation and stability. Negative regulation of VSMC migration (GO:1904753) is impaired in atherosclerosis, leading to excessive intimal thickening. Restenosis after angioplasty or stenting is driven by rapid VSMC migration and proliferation, and enhancing negative regulatory pathways could prevent this complication. Key mediators include LRP1, whose loss accelerates lesion formation, and shear stress, which is often disturbed at bifurcations where plaques preferentially form.
Hypertension and Vascular Remodeling
Hypertension induces vascular remodeling, in part through increased VSMC migration and hypertrophy. Negative regulators such as KCNMB1 help maintain vascular tone and quiescence; reduced KCNMB1 expression is associated with a synthetic VSMC phenotype and increased apoptosis, contributing to vascular dysfunction. Sclerostin has also been linked to vascular pathophysiology in hypertension and chronic kidney disease, potentially affecting VSMC behavior. Targeting these pathways could mitigate hypertensive vascular damage.
Cancer and Tumor Vasculature
Although GO:1904753 is primarily studied in cardiovascular contexts, VSMC-like pericytes in tumor vasculature can influence tumor growth and metastasis. Negative regulation of pericyte migration may stabilize tumor vessels and improve drug delivery. However, direct evidence linking GO:1904753 to cancer is limited, and most cancer-related studies focus on stromal signatures rather than VSMC migration specifically. Further research is needed to clarify the role of VSMC migration regulation in oncology.
From negative regulation of vascular associated smooth muscle cell migration-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X negatively regulate VSMC migration? | CRISPR knockout of gene X in primary VSMCs or cell lines, followed by migration assays |
| Does a point mutation in gene Y alter its anti-migratory function? | CRISPR point mutation knock-in in VSMCs |
| Does overexpression of gene Z suppress VSMC migration? | Lentiviral or CRISPR activation overexpression in VSMCs |
| Does a tagged version of protein W localize correctly and interact with partners? | CRISPR knock-in of epitope tag (e.g., FLAG, HA) in VSMCs |
| What is the transcriptomic signature of negative regulation? | RNA-seq of VSMCs under shear stress or with gene knockout |
| Can a drug enhance negative regulation? | High-throughput migration screen with small molecule libraries in VSMCs |
How to Study the negative regulation of vascular associated smooth muscle cell migration Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Transwell migration assay | Number of cells migrating through a membrane | Screening for negative regulators |
| Scratch wound assay | Rate of cell monolayer closure | Kinetic analysis of migration inhibition |
| Shear stress bioreactor | VSMC migration under flow | Physiological negative regulation |
| RNA-seq | Global transcriptome changes | Identifying anti-migratory gene networks |
| Phosphoproteomics | Signaling pathway activation | Mapping inhibitory signaling |
| Live-cell imaging | Cytoskeletal dynamics and cell tracking | Visualizing migration arrest |
| CRISPR knockout | Gene function loss | Validating negative regulators |
| Proximity labeling (BioID) | Protein-protein interactions | Discovering LRP1 interactors |
Migration Assays
The gold standard for studying GO:1904753 is the transwell or scratch wound migration assay, where VSMC movement is quantified under various conditions. These assays can be combined with shear stress devices to mimic physiological flow. Boyden chamber assays are also used to assess chemotaxis. For high-throughput screening, automated live-cell imaging platforms track individual cell trajectories.
Transcriptomics and Epigenomics
RNA-seq and ATAC-seq can reveal the transcriptional programs underlying negative regulation of VSMC migration. Comparing quiescent versus migratory VSMCs identifies anti-migratory gene signatures. Single-cell RNA-seq of atherosclerotic plaques can pinpoint VSMC subpopulations with distinct migratory properties. Non-coding RNA profiling, such as lncRNA and miRNA arrays, has uncovered regulators like HIX003209 and miR-6089.
Proteomics and Interactomics
Mass spectrometry-based proteomics can identify protein complexes involved in negative regulation, such as LRP1-associated signaling hubs. Phosphoproteomics reveals signaling changes downstream of shear stress or receptor activation. Proximity labeling (BioID) with CRISPR knock-in of TurboID can map interactomes in living VSMCs.
Imaging and Functional Validation
Live-cell imaging of fluorescently tagged cytoskeletal proteins (e.g., actin, focal adhesion kinase) visualizes the dynamic changes during migration inhibition. Immunofluorescence of contractile markers (e.g., MYH11, ACTA2) confirms phenotypic maintenance. CRISPR knockout followed by rescue experiments validates causality.
How CRISPR Can Be Used to Study GO:1904753 negative regulation of vascular associated smooth muscle cell migration
Knockout
CRISPR knockout is used to delete candidate negative regulator genes in VSMCs to test whether their loss increases migration. For example, knocking out LRP1 or KCNMB1 in VSMCs followed by transwell assays can confirm their role in GO:1904753. Pooled CRISPR screens with migration readouts can identify novel anti-migratory genes.
Point Mutation
Point mutations can dissect specific domains or phosphorylation sites required for negative regulation. For instance, mutating TWIST1 domains via CRISPR base editing can reveal which residues are essential for suppressing VSMC migration. Similarly, point mutations in LRP1's intracellular domain can test its signaling contribution.
Knock-in
Knock-in of reporter tags (e.g., GFP, FLAG) into endogenous loci allows visualization and immunoprecipitation of negative regulators at physiological levels. CRISPR knock-in of a tag into KCNMB1 or LRP1 enables tracking of protein localization and interactions in live VSMCs. Knock-in of disease-associated variants can model their impact on migration.
Overexpression
CRISPR activation (CRISPRa) or lentiviral overexpression of candidate genes can test whether increased dosage enhances negative regulation of VSMC migration. Overexpressing miR-6089 or TWIST1 can suppress migration, while overexpressing HIX003209 promotes it. These models are useful for gain-of-function studies.
How EDITGENE Supports negative regulation of vascular associated smooth muscle cell migration Research
Researchers studying negative regulation of vascular associated smooth muscle cell migration-related genes often need to determine whether a candidate gene is causally involved in suppressing VSMC migration. EDITGENE provides a comprehensive suite of CRISPR-based services to accelerate this discovery process, from gene knockout to precise point mutations and knock-in models.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of vascular associated smooth muscle cell migration research.
Frequently Asked Questions About negative regulation of vascular associated smooth muscle cell migration
What is GO:1904753?
GO:1904753 is a Gene Ontology term for negative regulation of vascular associated smooth muscle cell migration, describing any process that stops, prevents, or reduces the frequency, rate, or extent of VSMC migration.
What genes are involved in negative regulation of vascular smooth muscle cell migration?
Key genes include LRP1, VLDLR, KCNMB1, TWIST1, and non-coding RNAs such as HIX003209 and miR-6089, as well as SOST (sclerostin).
How does blood shear stress inhibit VSMC migration?
Laminar shear stress activates endothelial and VSMC mechanotransduction pathways that suppress migratory signaling and promote a contractile phenotype.
What diseases are associated with dysregulated VSMC migration?
Atherosclerosis, restenosis after angioplasty, hypertension, and vascular remodeling are linked to impaired negative regulation of VSMC migration.
What experimental models are used to study GO:1904753?
Transwell migration assays, shear stress bioreactors, CRISPR knockout/knock-in in VSMCs, and animal models of restenosis are commonly used.
How can CRISPR help identify negative regulators of VSMC migration?
Pooled CRISPR knockout screens with migration readouts can systematically identify genes whose loss increases VSMC migration, revealing novel negative regulators.
What is the role of KCNMB1 in VSMC migration?
KCNMB1 encodes the BK channel beta-1 subunit; its reduced expression leads to VSMC phenotypic switching and apoptosis, indirectly promoting a migratory phenotype.
Does sclerostin affect vascular smooth muscle cells?
Sclerostin, encoded by SOST, is a Wnt antagonist that influences vascular pathophysiology and may modulate VSMC behavior, including migration.
What is the link between LRP1 and VSMC migration?
LRP1 is a member of the LDL receptor family that inhibits VSMC migration by modulating extracellular matrix interactions and intracellular signaling.
How does HIX003209 regulate VSMC migration?
HIX003209 is a long non-coding RNA that promotes VSMC migration and proliferation by sponging miR-6089, thereby relieving negative regulation.
Conclusion
GO:1904753, negative regulation of vascular associated smooth muscle cell migration, is a critical biological process that maintains vascular homeostasis and prevents pathological conditions such as atherosclerosis and restenosis. Key regulators include hemodynamic shear stress, lipoprotein receptors, ion channels, transcription factors, and non-coding RNAs. Understanding these mechanisms offers therapeutic opportunities to enhance negative regulation and combat cardiovascular disease. EDITGENE's CRISPR services provide powerful tools to dissect these pathways and identify novel targets for intervention.
References
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