GO:1905174 regulation of vascular associated smooth muscle cell dedifferentiation: Phenotypic Switching Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1905174 describes any process that modulates the frequency, rate or extent of vascular smooth muscle cell dedifferentiation, a biological_process ontology term.
• Vascular smooth muscle cell (VSMC) dedifferentiation is a hallmark of atherosclerosis and vascular remodeling, where contractile VSMCs transition to a synthetic, proliferative phenotype.
• Key molecular drivers include PDGFR, WNT5B, TGF-beta signaling, and secreted proteins such as tenascin-X, which regulate the dedifferentiation program.
• Premature cell senescence promotes VSMC phenotypic modulation and resistance to re-differentiation, linking aging to vascular disease.
• Trophoblast-derived factors at the maternal-fetal interface can regulate VSMC phenotype switching, implicating this process in placental disorders.
• CRISPR-based knockout, point mutation, knock-in, and overexpression models are essential to dissect causal genes in VSMC dedifferentiation.
Description
GO:1905174, regulation of vascular associated smooth muscle cell dedifferentiation, is a Gene Ontology biological_process term that encompasses any process modulating the frequency, rate or extent of vascular smooth muscle cell (VSMC) dedifferentiation. VSMCs are normally quiescent and contractile, but in response to injury or pathological cues they can dedifferentiate into a synthetic phenotype, a phenomenon known as phenotypic switching. This term is critical for researchers because VSMC dedifferentiation underlies the pathogenesis of atherosclerosis, restenosis, and other vascular diseases. Understanding the regulatory mechanisms of VSMC dedifferentiation is therefore essential for identifying therapeutic targets and developing interventions that stabilize the contractile phenotype. The process is regulated by a complex network of growth factors, transcription factors, and extracellular matrix components, with emerging evidence linking it to cellular senescence and metabolic reprogramming.
regulation of vascular associated smooth muscle cell dedifferentiation At A Glance
| GO ID | GO:1905174 |
|---|---|
| GO term | regulation of vascular associated smooth muscle cell dedifferentiation |
| Ontology | biological_process |
| Synonym | regulation of vascular smooth muscle cell dedifferentiation |
| Major function | Modulates the frequency, rate or extent of VSMC dedifferentiation |
| Related process | VSMC phenotypic switching in atherosclerosis and vascular remodeling |
| Key regulators | PDGFR, WNT5B, TGF-beta, tenascin-X, senescence pathways |
| Disease relevance | Atherosclerosis, arteriosclerosis, chronic thromboembolic pulmonary hypertension |
What Is GO:1905174?
According to the Gene Ontology, GO:1905174 is defined as any process that modulates the frequency, rate or extent of vascular smooth muscle cell dedifferentiation. In other words, it covers all molecular and cellular events that control the transition of a differentiated, contractile vascular smooth muscle cell back to a less differentiated, synthetic state. This regulation can be positive (promoting dedifferentiation) or negative (inhibiting dedifferentiation or promoting re-differentiation), and it is executed through signaling pathways, transcriptional programs, and cell-cell interactions.
Why Is regulation of vascular associated smooth muscle cell dedifferentiation Important in Cell Biology?
GO:1905174 is important because VSMC dedifferentiation is a central event in the pathogenesis of major cardiovascular diseases, including atherosclerosis, restenosis, and pulmonary hypertension. The ability to regulate this process could lead to new therapies that prevent or reverse vascular remodeling. Moreover, the term integrates diverse signaling inputs, from growth factors to extracellular matrix proteins, making it a hub for understanding how cells integrate environmental cues to change phenotype.
• VSMC dedifferentiation is a hallmark of atherosclerosis and contributes to plaque instability.
• Regulation of VSMC dedifferentiation influences vascular remodeling after injury.
• Premature senescence promotes VSMC phenotypic modulation and resistance to re-differentiation, linking aging to vascular disease.
• WNT5B promotes VSMC dedifferentiation via mitochondrial dynamics in chronic thromboembolic pulmonary hypertension.
• TGF-beta signaling, modulated by tenascin-X, inhibits vascular remodeling by suppressing dedifferentiation.
• PDGFR is a key driver of VSMC dedifferentiation and a target for compounds like Kanglexin.
• Secreted proteins from human aortic SMCs are associated with vascular disease and may serve as biomarkers.
• Trophoblast cells at the maternal-fetal interface can regulate VSMC phenotype switching, implicating this process in placental disorders.
• Understanding GO:1905174 can guide the development of CRISPR-based models to test causal genes.
• The term is essential for systems biology approaches to vascular disease.
What Happens During regulation of vascular associated smooth muscle cell dedifferentiation?
Initiation of dedifferentiation by growth factors and cytokines
In simple terms: Growth factors and cytokines tell the smooth muscle cell to stop being contractile and start dividing.
VSMC dedifferentiation is initiated by extracellular cues such as PDGF, WNT5B, and TGF-beta family members. PDGFR signaling promotes dedifferentiation and is a target for inhibitors like Kanglexin. WNT5B drives dedifferentiation via regulation of mitochondrial dynamics in chronic thromboembolic pulmonary hypertension. TGF-beta signaling, on the other hand, can inhibit vascular remodeling by promoting a contractile phenotype, as shown by loss of tenascin-X.
Transcriptional reprogramming and phenotypic switching
In simple terms: The cell switches which genes are turned on, losing contractile markers and gaining synthetic ones.
Dedifferentiation involves downregulation of contractile markers such as smooth muscle alpha-actin and upregulation of synthetic markers. This transcriptional reprogramming is regulated by transcription factors and epigenetic changes. Senescence promotes this phenotypic modulation and resistance to re-differentiation. The process is a key feature of atherosclerosis, where VSMCs transition to a synthetic state.
Role of cell-cell interactions and extracellular matrix
In simple terms: Other cells and the matrix around the smooth muscle cell can influence its decision to dedifferentiate.
Trophoblast cells at the maternal-fetal interface can regulate VSMC phenotype switching, suggesting that cell-cell interactions modulate dedifferentiation. Extracellular matrix components such as tenascin-X affect TGF-beta signaling and thereby inhibit vascular remodeling. Secreted proteins from human aortic SMCs are associated with vascular disease and may mediate paracrine regulation.
Metabolic and mitochondrial dynamics in dedifferentiation
In simple terms: Changes in how the cell produces energy can drive the dedifferentiation process.
WNT5B promotes VSMC dedifferentiation via mitochondrial dynamics regulation, indicating that metabolic reprogramming is part of the regulatory mechanism. This links dedifferentiation to cellular energy status and mitochondrial function.
Re-differentiation and therapeutic targeting
In simple terms: Scientists are trying to find ways to make dedifferentiated cells become contractile again.
Resistance to re-differentiation is a feature of senescent VSMCs. Compounds like Kanglexin can counter dedifferentiation and associated arteriosclerosis by inhibiting PDGFR. Understanding the regulation of dedifferentiation may allow therapeutic re-differentiation.
Key Genes Involved in GO:1905174 regulation of vascular associated smooth muscle cell dedifferentiation
The following genes and proteins are key regulators of vascular smooth muscle cell dedifferentiation, as supported by the cited literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| PDGFR | Promotes VSMC dedifferentiation | Target of Kanglexin; inhibition counters arteriosclerosis |
| WNT5B | Promotes dedifferentiation via mitochondrial dynamics | Implicated in chronic thromboembolic pulmonary hypertension |
| TGF-beta | Inhibits vascular remodeling; promotes contractile phenotype | Loss of tenascin-X increases TGF-beta signaling |
| Tenascin-X | Modulates TGF-beta signaling | Loss inhibits vascular remodeling |
| ACTA2 | Contractile marker; downregulated in dedifferentiation | Marker of VSMC phenotype |
| MYH11 | Contractile marker; downregulated in dedifferentiation | Marker of VSMC phenotype |
| KLF4 | Transcription factor promoting synthetic phenotype | Regulates VSMC phenotypic switching |
| MYOCD | Transcription factor promoting contractile phenotype | Opposes dedifferentiation |
| SERPINE1 | Secreted protein associated with vascular disease | Identified in secretome profiling |
| MMP2 | Matrix metalloproteinase; involved in remodeling | Secreted by synthetic VSMCs |
| IL-6 | Cytokine promoting inflammation and dedifferentiation | Secreted protein associated with vascular disease |
| TNF-alpha | Cytokine promoting dedifferentiation | Inflammatory mediator |
| p16INK4a | Senescence marker; promotes phenotypic modulation | Linked to resistance to re-differentiation |
| p21 | Senescence marker; promotes phenotypic modulation | Linked to resistance to re-differentiation |
| Notch | Signaling pathway regulating VSMC phenotype | Involved in phenotypic switching |
| Angiotensin II | Promotes dedifferentiation | Vasoactive peptide |
| PDGF-BB | Growth factor promoting dedifferentiation | Ligand for PDGFR |
How Is regulation of vascular associated smooth muscle cell dedifferentiation Regulated?
The regulation of VSMC dedifferentiation is mediated by multiple signaling pathways. PDGFR signaling promotes dedifferentiation and can be inhibited by Kanglexin. WNT5B regulates mitochondrial dynamics to drive dedifferentiation. TGF-beta signaling, enhanced by loss of tenascin-X, inhibits vascular remodeling. Senescence pathways, including p16 and p21, promote phenotypic modulation and resistance to re-differentiation. Trophoblast-derived factors at the maternal-fetal interface can also regulate VSMC phenotype switching.
regulation of vascular associated smooth muscle cell dedifferentiation and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| PDGFR | Atherosclerosis, arteriosclerosis | VSMC-specific knockout or overexpression in ApoE-/- mice |
| WNT5B | Chronic thromboembolic pulmonary hypertension | Knockdown or knockout in pulmonary artery SMCs |
| Tenascin-X | Vascular remodeling | Knockout mouse model |
| p16INK4a | Vascular aging, senescence | Senescence induction in VSMC cultures |
| TGF-beta | Vascular remodeling | TGF-beta receptor knockout or knock-in |
Atherosclerosis
VSMC dedifferentiation is a hallmark of atherosclerosis, where contractile VSMCs switch to a synthetic phenotype, contributing to plaque formation and instability. Key regulators include PDGFR and inflammatory cytokines.
Chronic thromboembolic pulmonary hypertension
WNT5B promotes VSMC dedifferentiation via mitochondrial dynamics in chronic thromboembolic pulmonary hypertension, highlighting a specific molecular mechanism in this disease.
Vascular aging and senescence
Premature cell senescence promotes VSMC phenotypic modulation and resistance to re-differentiation, linking aging to vascular disease.
Placental disorders
Trophoblast cells at the maternal-fetal interface regulate VSMC phenotype switching, suggesting a role in placental-derived fetal growth restriction.
From regulation of vascular associated smooth muscle cell dedifferentiation-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X promote VSMC dedifferentiation? | Knockout of gene X in primary VSMCs or mouse models |
| Does a point mutation in gene Y affect dedifferentiation? | Point mutation knock-in via CRISPR in VSMCs |
| Does overexpression of gene Z induce dedifferentiation? | Overexpression lentivirus or CRISPR activation in VSMCs |
| Does a tag on protein W affect its function in dedifferentiation? | Tagged knock-in (e.g., GFP) in VSMCs |
| Which genes regulate dedifferentiation in a high-throughput manner? | CRISPR library screening in VSMC lines |
| What are the transcriptomic changes during dedifferentiation? | RNA-seq of contractile vs synthetic VSMCs |
How to Study the regulation of vascular associated smooth muscle cell dedifferentiation Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Global gene expression changes | Identify markers and pathways in dedifferentiation |
| Secretome profiling | Secreted proteins | Discover biomarkers and paracrine factors |
| Immunofluorescence | Protein localization and expression | Assess contractile vs synthetic phenotype |
| Western blot | Protein levels | Quantify contractile markers |
| CRISPR knockout | Gene function loss | Test causal role of candidate genes |
| CRISPR knock-in | Specific mutations or tags | Model point mutations or track proteins |
| CRISPR activation | Gene overexpression | Study gain-of-function in dedifferentiation |
| Mitochondrial dynamics assays | Mitochondrial morphology and function | Link metabolism to dedifferentiation |
Transcriptomic profiling
RNA-seq can identify global changes in gene expression during VSMC dedifferentiation, revealing contractile-to-synthetic markers.
Proteomic and secretome analysis
Secreted protein profiling of human aortic SMCs identifies vascular disease associations and potential biomarkers.
Imaging and phenotypic assays
Immunofluorescence for contractile markers (e.g., ACTA2, MYH11) and proliferation assays can quantify dedifferentiation.
CRISPR-based functional genomics
CRISPR knockout, knock-in, and overexpression models allow causal testing of candidate genes in VSMC dedifferentiation.
How CRISPR Can Be Used to Study GO:1905174 regulation of vascular associated smooth muscle cell dedifferentiation
Knockout
CRISPR knockout of candidate genes such as PDGFR or WNT5B in VSMCs can determine whether they are required for dedifferentiation. Knockout models help establish causality.
Point Mutation
Introducing specific point mutations (e.g., in TGF-beta signaling components) via CRISPR can model human genetic variants and assess their impact on dedifferentiation.
Knock-in
Knock-in of reporter tags (e.g., GFP) or disease-associated alleles allows tracking of protein expression and function during dedifferentiation.
Overexpression
CRISPR activation or lentiviral overexpression of genes like WNT5B can drive dedifferentiation and test sufficiency.
How EDITGENE Supports regulation of vascular associated smooth muscle cell dedifferentiation Research
Researchers studying regulation of vascular associated smooth muscle cell dedifferentiation-related genes often need to determine whether a candidate gene is causally involved in the phenotypic switch. This requires precise genetic manipulation in relevant cell models, such as human aortic smooth muscle cells or mouse VSMCs. EDITGENE provides a comprehensive suite of CRISPR services to enable such studies, from knockout to knock-in and library screening.
Contact EDITGENE today to design your custom CRISPR model for regulation of vascular associated smooth muscle cell dedifferentiation research.
Frequently Asked Questions About regulation of vascular associated smooth muscle cell dedifferentiation
What is GO:1905174?
GO:1905174 is a Gene Ontology biological_process term defined as any process that modulates the frequency, rate or extent of vascular smooth muscle cell dedifferentiation.
What is vascular smooth muscle cell dedifferentiation?
It is the process by which contractile vascular smooth muscle cells revert to a synthetic, proliferative phenotype, commonly seen in atherosclerosis and vascular injury.
What genes are involved in regulation of vascular associated smooth muscle cell dedifferentiation?
Key genes include PDGFR, WNT5B, TGF-beta, tenascin-X, and senescence markers such as p16 and p21.
How is VSMC dedifferentiation regulated?
It is regulated by growth factors (PDGF, WNT5B), cytokines (TGF-beta), extracellular matrix components (tenascin-X), and cellular senescence pathways.
What diseases are associated with VSMC dedifferentiation?
Atherosclerosis, chronic thromboembolic pulmonary hypertension, vascular aging, and placental disorders.
What research methods are used to study GO:1905174?
RNA-seq, secretome profiling, immunofluorescence, and CRISPR-based knockout, knock-in, and overexpression models.
How can CRISPR help study VSMC dedifferentiation?
CRISPR allows precise knockout, point mutation, knock-in, and overexpression of candidate genes to test their causal role in dedifferentiation.
What is the role of PDGFR in VSMC dedifferentiation?
PDGFR signaling promotes dedifferentiation, and its inhibition by Kanglexin counters arteriosclerosis.
How does WNT5B regulate VSMC dedifferentiation?
WNT5B promotes dedifferentiation via regulation of mitochondrial dynamics in chronic thromboembolic pulmonary hypertension.
What is the link between senescence and VSMC dedifferentiation?
Premature cell senescence promotes VSMC phenotypic modulation and resistance to re-differentiation.
Conclusion
GO:1905174, regulation of vascular associated smooth muscle cell dedifferentiation, is a critical biological process in vascular biology and disease. Understanding its molecular regulators, such as PDGFR, WNT5B, and TGF-beta, offers opportunities for therapeutic intervention in atherosclerosis and related disorders. CRISPR-based models are indispensable for dissecting these mechanisms and translating findings into clinical applications.
References
- 1. Chen R et al.. 2023. Phenotypic Switching of Vascular Smooth Muscle Cells in Atherosclerosis.. J Am Heart Assoc 12(20):e031121 PMID: 37815057
- 2. Burton GJ et al.. 2018. Pathophysiology of placental-derived fetal growth restriction.. Am J Obstet Gynecol 218(2S):S745-S761 PMID: 29422210
- 3. Kaistha A et al.. 2025. Premature cell senescence promotes vascular smooth muscle cell phenotypic modulation and resistance to re-differentiation.. Cardiovasc Res 121(9):1448-1463 PMID: 40493738
- 4. Liang G et al.. 2024. Loss of Smooth Muscle Tenascin-X Inhibits Vascular Remodeling Through Increased TGF-β Signaling.. Arterioscler Thromb Vasc Biol 44(8):1748-1763 PMID: 38934115
- 5. Yang S et al.. 2024. Kanglexin counters vascular smooth muscle cell dedifferentiation and associated arteriosclerosis through inhibiting PDGFR.. Phytomedicine 130:155704 PMID: 38759316
- 6. Aherrahrou R et al.. 2024. Secreted Protein Profiling of Human Aortic Smooth Muscle Cells Identifies Vascular Disease Associations.. Arterioscler Thromb Vasc Biol 44(4):898-914 PMID: 38328934
- 7. Wang F et al.. 2022. WNT5B promotes vascular smooth muscle cell dedifferentiation via mitochondrial dynamics regulation in chronic thromboembolic pulmonary hypertension.. J Cell Physiol 237(1):789-803 PMID: 34368954
- 8. Nandy D et al.. 2020. Molecular regulation of vascular smooth muscle cell phenotype switching by trophoblast cells at the maternal-fetal interface.. Placenta 93:64-73 PMID: 32250741
