GO:1905461 positive regulation of vascular associated smooth muscle cell apoptotic process: Apoptosis Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1905461 describes any process that activates or increases the frequency, rate or extent of vascular associated smooth muscle cell (VSMC) apoptosis.
• VSMC apoptosis is a double-edged sword: it stabilizes atherosclerotic plaques when balanced, but excessive apoptosis drives plaque instability, aneurysm and dissection.
• Key molecular drivers include hydrogen sulfide/TFEB-mediated autophagy, Ncf1/STING signaling, KCNMB1 loss, LTβR, Smad2/MET, and calcium channel activity.
• Dysregulated VSMC apoptosis is implicated in atherosclerosis, abdominal aortic aneurysm, aortic dissection, and vascular remodeling.
• CRISPR knockout, point mutation, knock-in and overexpression models are essential to establish causality between candidate genes and VSMC apoptosis.
• EDITGENE provides end-to-end CRISPR cell model and library screening services to dissect GO:1905461-related mechanisms.
Description
The Gene Ontology term GO:1905461, positive regulation of vascular associated smooth muscle cell apoptotic process, captures the biological processes that activate or increase the frequency, rate or extent of apoptosis in vascular associated smooth muscle cells (VSMCs). VSMCs are the predominant cell type in the arterial media, and their programmed death is a tightly regulated event that influences vascular wall integrity, plaque stability and remodeling. Understanding the positive regulators of VSMC apoptosis is therefore central to vascular biology and to diseases such as atherosclerosis, aneurysm and dissection. Mechanistically, positive regulation of VSMC apoptosis can be driven by diverse signals, including autophagic flux modulation via the TFEB transcription factor, innate immune activation through the STING pathway, loss of potassium channel subunit KCNMB1, and cytokine receptor LTβR signaling. These pathways converge on mitochondrial outer membrane permeabilization, caspase activation and DNA fragmentation, the canonical hallmarks of apoptosis. Because VSMC apoptosis is context-dependent, distinguishing protective from detrimental regulation requires precise genetic models. For researchers, GO:1905461 provides a standardized framework to annotate genes and pathways that promote VSMC death. This article synthesizes authoritative QuickGO data and verified PubMed literature to outline the definition, mechanisms, key genes, disease links and experimental strategies, including CRISPR-based knockout, point mutation, knock-in and overexpression models, for studying this process.
positive regulation of vascular associated smooth muscle cell apoptotic process At A Glance
| GO ID | GO:1905461 |
|---|---|
| GO term | positive regulation of vascular associated smooth muscle cell apoptotic process |
| Ontology | biological_process |
| Synonym | activation of VSMC apoptosis; positive regulation of VSMC apoptotic process; upregulation of vascular smooth muscle cell apoptosis |
| Major function | Activates or increases the frequency, rate or extent of apoptosis in vascular associated smooth muscle cells |
| Related process | Apoptotic process; regulation of cell death; vascular smooth muscle cell homeostasis |
| Disease relevance | Atherosclerosis, abdominal aortic aneurysm, aortic dissection, vascular remodeling |
| Research tools | CRISPR knockout, point mutation, knock-in, overexpression, library screening |
What Is GO:1905461?
GO:1905461 is a biological process term defined as any process that activates or increases the frequency, rate or extent of vascular associated smooth muscle cell apoptotic process. In other words, it encompasses molecular events that push VSMCs toward programmed cell death, as opposed to negative regulation that protects them. The term is a child of positive regulation of apoptotic process and is specific to vascular associated smooth muscle cells, distinguishing it from apoptosis regulation in other cell types.
Why Is positive regulation of vascular associated smooth muscle cell apoptotic process Important in Cell Biology?
GO:1905461 is important because VSMC apoptosis is a critical determinant of vascular stability and disease progression. In atherosclerosis, balanced VSMC apoptosis can limit plaque growth, but excessive apoptosis promotes necrotic core formation and plaque rupture. In aortic aneurysm and dissection, loss of VSMCs weakens the vessel wall and accelerates dilation and rupture. Thus, identifying positive regulators of VSMC apoptosis offers therapeutic targets and biomarkers for major cardiovascular diseases.
• VSMC apoptosis is a hallmark of advanced atherosclerotic plaques and contributes to plaque instability.
• Excessive VSMC apoptosis drives medial degeneration in abdominal aortic aneurysm and aortic dissection.
• Hydrogen sulfide produced by VSMCs promotes plaque stability via TFEB-mediated autophagy, highlighting protective versus detrimental apoptosis regulation.
• Ncf1 knockout in smooth muscle cells exacerbates angiotensin II-induced aortic aneurysm and dissection by activating the STING pathway, linking innate immunity to VSMC death.
• Reduced KCNMB1 expression leads to VSMC phenotypic switch and apoptosis, implicating ion channels in GO:1905461.
• LTβR signaling modulates VSMC apoptosis and immune cell infiltration in atherosclerosis.
• Smad2 inhibition of MET transcription potentiates human VSMC apoptosis, revealing a TGF-β-related mechanism.
• Calcium channel regulation by statins and calcium channel blockers affects VSMC apoptosis and vascular tone.
• Neutrophil gelatinase-associated lipocalin may influence abdominal aortic aneurysm development partly through VSMC apoptosis.
• CRISPR-based models enable causal testing of candidate genes in VSMC apoptosis for drug discovery.
What Happens During positive regulation of vascular associated smooth muscle cell apoptotic process?
Initiation by Stress and Cytokine Signals
In simple terms: Cells receive death signals from stress or inflammation.
Positive regulation of VSMC apoptosis begins when extracellular or intracellular stressors activate death receptors or stress pathways. For example, LTβR signaling modulates VSMC apoptosis and immune cell infiltration in atherosclerosis. In aortic aneurysm, Ncf1 deficiency in smooth muscle cells activates the STING pathway, which promotes VSMC apoptosis and exacerbates angiotensin II-induced aortic aneurysm and dissection. These initiating signals converge on transcriptional programs that sensitize VSMCs to death.
Autophagy and TFEB-Mediated Regulation
In simple terms: Autophagy can either protect or kill cells depending on context.
VSMC-derived hydrogen sulfide promotes atherosclerotic plaque stability via TFEB (transcription factor EB)-mediated autophagy. This pathway illustrates that positive regulation of VSMC apoptosis can be counterbalanced by autophagic survival mechanisms; when autophagy is insufficient, apoptosis proceeds. TFEB coordinates lysosomal and autophagic gene expression, and its modulation affects VSMC fate in plaques.
Mitochondrial Outer Membrane Permeabilization and Caspase Activation
In simple terms: Mitochondria release factors that activate executioner caspases.
A common effector step in VSMC apoptosis is mitochondrial-dependent apoptosis, as shown in pericyte-myofibroblast transition where FUT8 upregulates CD36 and core fucosylation accelerates mitochondrial-dependent apoptosis. In VSMCs, Smad2 inhibition of MET transcription potentiates human VSMC apoptosis, likely through mitochondrial and caspase-dependent pathways. These events lead to cytochrome c release, apoptosome formation and caspase-3 activation.
Ion Channel and Calcium Signaling
In simple terms: Calcium levels and ion channels control cell survival.
Reduced expression of KCNMB1 leads to VSMC phenotypic switch and apoptosis, indicating that potassium channel subunits regulate VSMC survival. Calcium channel regulation in VSMCs is also modulated by statins and calcium channel blockers, which can influence apoptosis and vascular tone. Thus, ion flux and calcium signaling are integral to positive regulation of VSMC apoptosis.
Phenotypic Switch and Vascular Remodeling
In simple terms: VSMCs change identity and die, weakening the vessel wall.
VSMC apoptosis is often accompanied by phenotypic switching from a contractile to a synthetic state, as seen with KCNMB1 loss. In abdominal aortic aneurysm, neutrophil gelatinase-associated lipocalin may contribute to VSMC apoptosis and wall degeneration. This remodeling process links GO:1905461 to clinical outcomes such as aneurysm rupture and plaque instability.
Key Genes Involved in GO:1905461 positive regulation of vascular associated smooth muscle cell apoptotic process
The following genes and proteins have been experimentally linked to positive regulation of vascular associated smooth muscle cell apoptotic process in the verified literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| TFEB | Transcription factor EB; mediates autophagy in VSMCs | Hydrogen sulfide promotes plaque stability via TFEB-mediated autophagy |
| Ncf1 | Neutrophil cytosolic factor 1; regulates STING pathway | Ncf1 knockout in SMCs exacerbates aortic aneurysm via STING |
| STING | Stimulator of interferon genes; innate immune signaling | Activated by Ncf1 deficiency to promote VSMC apoptosis |
| FUT8 | Fucosyltransferase 8; core fucosylation of CD36 | Upregulates CD36 and accelerates mitochondrial-dependent apoptosis |
| CD36 | Scavenger receptor; fatty acid translocase | Core fucosylation by FUT8 links to apoptosis |
| NGAL | Neutrophil gelatinase-associated lipocalin | Potential role in abdominal aortic aneurysm and VSMC apoptosis |
| KCNMB1 | Potassium calcium-activated channel subfamily M regulatory beta 1 | Reduced expression leads to VSMC phenotypic switch and apoptosis |
| LTβR | Lymphotoxin beta receptor; cytokine signaling | Paeonol attenuates atherosclerosis by reducing LTβR and VSMC apoptosis |
| Smad2 | TGF-β signaling effector; inhibits MET transcription | Smad2 inhibition potentiates human VSMC apoptosis |
| MET | Hepatocyte growth factor receptor | Smad2 inhibition of MET transcription potentiates apoptosis |
| Cav1.2 | L-type calcium channel subunit | Calcium channel regulation affects VSMC apoptosis |
| Caspase-3 | Executioner caspase | Effector of mitochondrial-dependent apoptosis |
| Bax | Pro-apoptotic Bcl-2 family member | Mitochondrial outer membrane permeabilization |
| Bcl-2 | Anti-apoptotic Bcl-2 family member | Counterbalances apoptosis |
| Cytochrome c | Mitochondrial electron carrier; apoptosome component | Released during mitochondrial apoptosis |
| ATG5 | Autophagy-related 5 | Autophagy pathway linked to TFEB |
| SQSTM1/p62 | Autophagy receptor | Autophagic flux marker |
| LC3B | Autophagosome marker | Autophagy monitoring |
How Is positive regulation of vascular associated smooth muscle cell apoptotic process Regulated?
Positive regulation of VSMC apoptosis is controlled by a network of signaling pathways. TFEB-mediated autophagy acts as a survival mechanism that can suppress apoptosis in VSMCs. The STING pathway, activated by Ncf1 deficiency, promotes apoptosis and aortic aneurysm. LTβR signaling modulates VSMC apoptosis and immune infiltration. Smad2 inhibition of MET transcription potentiates apoptosis. Ion channels such as KCNMB1 and calcium channels influence survival. These pathways are potential therapeutic targets for modulating GO:1905461.
positive regulation of vascular associated smooth muscle cell apoptotic process and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| TFEB | Atherosclerosis plaque stability | VSMC-specific TFEB knockout or overexpression |
| Ncf1 | Aortic aneurysm and dissection | Smooth muscle cell-specific Ncf1 knockout |
| KCNMB1 | Vascular remodeling | KCNMB1 knockdown or knockout in VSMCs |
| LTβR | Atherosclerosis | LTβR knockout or overexpression in VSMCs |
| Smad2 | VSMC apoptosis | Smad2 point mutation or knockout |
Atherosclerosis and Plaque Stability
VSMC apoptosis is a key feature of advanced atherosclerotic plaques. Hydrogen sulfide derived from VSMCs promotes plaque stability via TFEB-mediated autophagy, suggesting that enhancing autophagy may limit excessive apoptosis. Paeonol attenuates atherosclerosis by regulating VSMC apoptosis and immune cell infiltration through reducing LTβR expression. Thus, GO:1905461 is directly linked to plaque progression and rupture risk.
Abdominal Aortic Aneurysm and Aortic Dissection
Excessive VSMC apoptosis weakens the aortic wall and contributes to aneurysm and dissection. Ncf1 knockout in smooth muscle cells exacerbates angiotensin II-induced aortic aneurysm and dissection by activating the STING pathway. Neutrophil gelatinase-associated lipocalin may also play a role in abdominal aortic aneurysm development. These findings highlight GO:1905461 as a driver of aortic pathology.
Vascular Remodeling and Phenotypic Switch
Reduced KCNMB1 expression leads to VSMC phenotypic switch and apoptosis, linking ion channel dysfunction to vascular remodeling. Calcium channel regulation by statins and calcium channel blockers further modulates VSMC apoptosis and vascular tone. These mechanisms contribute to hypertension, restenosis and other remodeling diseases.
Kidney Injury and Pericyte Transition
FUT8 upregulates CD36 and its core fucosylation to accelerate pericyte-myofibroblast transition through mitochondrial-dependent apoptosis during AKI-CKD. Although pericytes are not VSMCs, this study illustrates conserved mitochondrial apoptosis mechanisms that may inform VSMC research.
From positive regulation of vascular associated smooth muscle cell apoptotic process-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of Ncf1 in VSMCs promote apoptosis via STING? | Smooth muscle cell-specific Ncf1 knockout |
| Does TFEB-mediated autophagy protect VSMCs from apoptosis? | VSMC-specific TFEB knockout or overexpression |
| Does KCNMB1 reduction cause VSMC apoptosis? | KCNMB1 knockdown or knockout in VSMCs |
| Does LTβR signaling modulate VSMC apoptosis? | LTβR knockout or overexpression in VSMCs |
| Does Smad2 inhibition of MET potentiate apoptosis? | Smad2 point mutation or MET knock-in |
| Do calcium channel variants affect VSMC survival? | Cav1.2 point mutation knock-in |
How to Study the positive regulation of vascular associated smooth muscle cell apoptotic process Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout | Gene function loss | Identify positive regulators of VSMC apoptosis |
| RNA-seq | Transcriptome changes | Discover apoptosis-related pathways |
| Proteomics | Protein expression and modifications | Detect core fucosylation of CD36 |
| Annexin V/PI flow cytometry | Apoptosis rate | Quantify VSMC apoptosis |
| TUNEL assay | DNA fragmentation | Detect apoptotic VSMCs in tissue |
| Caspase-3 activity assay | Caspase activation | Confirm mitochondrial apoptosis |
| Immunofluorescence | Protein localization | Visualize STING or TFEB in VSMCs |
| Western blot | Protein expression | Measure Bcl-2, Bax, LC3B |
CRISPR Knockout Screens
Genome-wide CRISPR knockout screens can identify positive regulators of VSMC apoptosis. For example, Ncf1 knockout in smooth muscle cells exacerbated aortic aneurysm via STING activation, demonstrating the power of knockout models. KCNMB1 reduction was linked to VSMC apoptosis using knockdown approaches.
Transcriptomic and Proteomic Profiling
RNA-seq and proteomics can reveal gene expression changes during VSMC apoptosis. TFEB-mediated autophagy was studied using autophagy markers and transcriptional profiling. FUT8 and CD36 core fucosylation were analyzed by proteomics and functional assays.
Apoptosis Assays
Annexin V/PI staining, TUNEL, caspase-3 activity and mitochondrial membrane potential assays are standard to quantify VSMC apoptosis. These methods were used to show Smad2 inhibition potentiates human VSMC apoptosis.
Imaging and Histology
Immunohistochemistry and immunofluorescence can detect apoptotic VSMCs in tissue sections. Plaque stability and VSMC apoptosis were assessed in atherosclerosis models. Aortic aneurysm tissues were analyzed for STING pathway activation.
How CRISPR Can Be Used to Study GO:1905461 positive regulation of vascular associated smooth muscle cell apoptotic process
Knockout
CRISPR knockout of candidate genes in VSMCs can determine whether they are required for positive regulation of apoptosis. For example, Ncf1 knockout in smooth muscle cells exacerbated aortic aneurysm via STING, showing that loss of Ncf1 promotes apoptosis. KCNMB1 knockout or knockdown leads to VSMC phenotypic switch and apoptosis.
Point Mutation
Point mutations can mimic disease-associated variants or disrupt specific phosphorylation sites. Smad2 inhibition of MET transcription potentiates apoptosis, and point mutations in Smad2 could test this mechanism. Calcium channel point mutations may alter VSMC survival.
Knock-in
Knock-in of tagged or mutant alleles allows precise tracking of proteins. Tagged TFEB knock-in could monitor autophagy flux in VSMCs. Knock-in of mutant STING could test its role in apoptosis.
Overexpression
Overexpression of pro-apoptotic genes such as Bax or LTβR can induce VSMC apoptosis. Overexpression of TFEB may protect VSMCs by enhancing autophagy. These models help validate gain-of-function effects.
How EDITGENE Supports positive regulation of vascular associated smooth muscle cell apoptotic process Research
Researchers studying positive regulation of vascular associated smooth muscle cell apoptotic process-related genes often need to determine whether a candidate gene is causally involved in VSMC death or merely correlated with it. EDITGENE provides CRISPR-based cell model services to establish causality through knockout, point mutation, knock-in and overexpression, as well as library screening and bioinformatics support.
Contact EDITGENE today to design your custom CRISPR model for positive regulation of vascular associated smooth muscle cell apoptotic process research.
Frequently Asked Questions About positive regulation of vascular associated smooth muscle cell apoptotic process
What is GO:1905461?
GO:1905461 is the Gene Ontology term for positive regulation of vascular associated smooth muscle cell apoptotic process, defined as any process that activates or increases the frequency, rate or extent of VSMC apoptosis.
What genes are involved in positive regulation of vascular associated smooth muscle cell apoptotic process?
Key genes include TFEB, Ncf1, STING, FUT8, CD36, KCNMB1, LTβR, Smad2, MET, and calcium channel subunits.
How is VSMC apoptosis regulated?
VSMC apoptosis is regulated by autophagy (TFEB), innate immune signaling (STING), cytokine receptors (LTβR), TGF-β signaling (Smad2/MET), and ion channels (KCNMB1, calcium channels).
Why is VSMC apoptosis important in atherosclerosis?
Excessive VSMC apoptosis promotes necrotic core formation and plaque instability, while balanced apoptosis may limit plaque growth.
What diseases are linked to GO:1905461?
Atherosclerosis, abdominal aortic aneurysm, aortic dissection, and vascular remodeling are linked to dysregulated VSMC apoptosis.
How can CRISPR help study VSMC apoptosis?
CRISPR knockout, point mutation, knock-in and overexpression models can establish causal roles of genes in VSMC apoptosis.
What is the role of Ncf1 in VSMC apoptosis?
Ncf1 knockout in smooth muscle cells exacerbates angiotensin II-induced aortic aneurysm and dissection by activating the STING pathway, promoting apoptosis.
What is the role of TFEB in VSMC apoptosis?
TFEB mediates autophagy in VSMCs; hydrogen sulfide promotes plaque stability via TFEB-mediated autophagy, which can suppress apoptosis.
How is KCNMB1 related to VSMC apoptosis?
Reduced KCNMB1 expression leads to VSMC phenotypic switch and apoptosis, implicating potassium channels in survival.
What methods are used to measure VSMC apoptosis?
Common methods include Annexin V/PI flow cytometry, TUNEL, caspase-3 activity, and mitochondrial membrane potential assays.
Conclusion
GO:1905461, positive regulation of vascular associated smooth muscle cell apoptotic process, is a critical biological process in vascular health and disease. Its dysregulation contributes to atherosclerosis, aneurysm and dissection, making it a prime target for therapeutic intervention. Understanding the molecular players such as TFEB, Ncf1, KCNMB1, LTβR and Smad2 provides a roadmap for future research. EDITGENE's CRISPR services, including knockout, point mutation, knock-in, overexpression and library screening, empower researchers to dissect this pathway with precision and accelerate the development of new treatments for vascular diseases.
References
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- 2. Liu H et al.. 2024. Ncf1 knockout in smooth muscle cells exacerbates angiotensin II-induced aortic aneurysm and dissection by activating the STING pathway.. Cardiovasc Res 120(9):1081-1096 PMID: 38639325
- 3. Shang Y et al.. 2024. FUT8 upregulates CD36 and its core fucosylation to accelerate pericyte-myofibroblast transition through the mitochondrial-dependent apoptosis pathway during AKI-CKD.. Mol Med 30(1):222 PMID: 39563263
- 4. Groeneveld ME et al.. 2019. The Potential Role of Neutrophil Gelatinase-Associated Lipocalin in the Development of Abdominal Aortic Aneurysms.. Ann Vasc Surg 57:210-219 PMID: 30684630
- 5. Liu H et al.. 2025. Reduced expression of KCNMB1 leads to vascular smooth muscle cell phenotypic switch and apoptosis.. Biochem Pharmacol 241:117151 PMID: 40653026
- 6. Liang Y et al.. 2024. Paeonol attenuates atherosclerosis by regulating vascular smooth muscle cells apoptosis and modulating immune cells infiltration through reducing LTβR expression.. Phytomedicine 135:156196 PMID: 39520955
- 7. Xie X et al.. 2021. Smad2 inhibition of MET transcription potentiates human vascular smooth muscle cell apoptosis.. Atheroscler Plus 44:31-42 PMID: 35445204
- 8. Clunn GF et al.. 2010. Calcium channel regulation in vascular smooth muscle cells: synergistic effects of statins and calcium channel blockers.. Int J Cardiol 139(1):2-6 PMID: 19523699
