GO:1905149 positive regulation of smooth muscle hypertrophy: Signaling Pathways, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1905149 describes any process that activates or increases the frequency, rate or extent of smooth muscle hypertrophy, a biological process central to vascular remodeling and hypertensive disease.
• Smooth muscle hypertrophy involves increases in cell size and protein content, often driven by cyclic nucleotide signaling, Akt/mTOR pathways, and MAP kinase cascades.
• Key regulators include B2M, LR11, p21Waf-1, and components of the cGMP/PDE system, which modulate smooth muscle cell growth in pulmonary and systemic hypertension.
• Dysregulated positive regulation of smooth muscle hypertrophy contributes to pulmonary arterial hypertension, heart failure with preserved ejection fraction, and aortic remodeling.
• CRISPR-based knockout, point mutation, knock-in, and overexpression models enable causal dissection of genes controlling smooth muscle hypertrophy.
• Therapeutic strategies targeting aldosterone, cyclic nucleotide phosphodiesterases, and B2M are being explored to modulate smooth muscle hypertrophy in cardiovascular disease.
Description
GO:1905149, positive regulation of smooth muscle hypertrophy, is a Gene Ontology biological process term that encompasses any molecular event or pathway that activates or increases the frequency, rate, or extent of smooth muscle hypertrophy. Smooth muscle hypertrophy refers to an increase in the size of individual smooth muscle cells, a hallmark of vascular remodeling in conditions such as hypertension and pulmonary arterial hypertension. This process is distinct from hyperplasia, as it primarily involves cell enlargement rather than proliferation, although the two can co-occur. Understanding the positive regulation of smooth muscle hypertrophy is critical for researchers studying cardiovascular pathology, as excessive smooth muscle growth contributes to vessel wall thickening, increased vascular resistance, and organ dysfunction. The term is supported by experimental evidence from studies on cyclic nucleotide signaling, proteomic regulators like B2M, and lipoprotein receptor family members such as LR11. This article synthesizes authoritative QuickGO data and verified PubMed literature to provide a research-grade overview of the mechanisms, genes, diseases, and experimental models associated with GO:1905149.
positive regulation of smooth muscle hypertrophy At A Glance
| GO ID | GO:1905149 |
|---|---|
| GO term | positive regulation of smooth muscle hypertrophy |
| Ontology | biological_process |
| Synonym | activation of smooth muscle hypertrophy; up regulation of smooth muscle hypertrophy; up-regulation of smooth muscle hypertrophy; upregulation of smooth muscle hypertrophy |
| Major function | Activates or increases the frequency, rate or extent of smooth muscle hypertrophy |
| Related processes | Smooth muscle cell growth, vascular remodeling, hypertension, pulmonary arterial hypertension |
| Key regulators | B2M, LR11, p21Waf-1, cGMP/PDE signaling, Akt/MAPK pathways |
| Disease relevance | Pulmonary hypertension, heart failure with preserved ejection fraction, aortic remodeling |
What Is GO:1905149?
According to the Gene Ontology, GO:1905149 is defined as any process that activates or increases the frequency, rate or extent of smooth muscle hypertrophy. In other words, it includes all molecular signals, pathways, and cellular events that promote the enlargement of smooth muscle cells, a key adaptive or maladaptive response in vascular and visceral tissues.
Why Is positive regulation of smooth muscle hypertrophy Important in Cell Biology?
Positive regulation of smooth muscle hypertrophy is critically important because excessive or dysregulated smooth muscle growth underlies major cardiovascular diseases, including pulmonary arterial hypertension, systemic hypertension, and heart failure with preserved ejection fraction. Identifying the molecular drivers of this process can reveal therapeutic targets and biomarkers, as demonstrated by studies on B2M in pulmonary hypertension and LR11 in hypoxia-induced pulmonary arterial smooth muscle cell proliferation. Moreover, understanding how cyclic nucleotide signaling and phosphodiesterases modulate smooth muscle hypertrophy offers opportunities for pharmacological intervention.
• Drives vascular remodeling in pulmonary arterial hypertension and systemic hypertension.
• Contributes to heart failure with preserved ejection fraction through pulmonary vascular changes.
• Involved in aortic remodeling and smooth muscle cell apoptosis regulation.
• Modulated by cyclic GMP and cyclic AMP signaling pathways, which are drug targets.
• Regulated by proteomic factors such as B2M, identified via plasma proteomics.
• Influenced by lipoprotein receptor LR11 in hypoxia-induced pulmonary arterial smooth muscle cells.
• p21Waf-1 overexpression affects smooth muscle cell proliferation, differentiation, and size.
• Aldosterone antagonism may impact smooth muscle hypertrophy in heart failure.
• Phosphodiesterase inhibitors are therapeutic candidates for modulating vascular smooth muscle growth.
• CRISPR models enable causal testing of candidate genes in smooth muscle hypertrophy.
What Happens During positive regulation of smooth muscle hypertrophy?
Initiation by Growth Factors and Neurohumoral Signals
In simple terms: The process starts when external signals tell smooth muscle cells to grow larger.
Positive regulation of smooth muscle hypertrophy is initiated by neurohumoral factors, growth factors, and mechanical stress that activate receptors on smooth muscle cells. For example, in pulmonary hypertension, circulating factors such as B2M can stimulate signaling cascades that promote smooth muscle cell enlargement. Similarly, aldosterone and other neurohumoral mediators contribute to vascular remodeling in heart failure. These initial signals converge on intracellular pathways that drive hypertrophic gene expression.
Cyclic Nucleotide Signaling and Phosphodiesterase Regulation
In simple terms: Cyclic nucleotides like cGMP and cAMP act as brakes or accelerators on smooth muscle growth.
Cyclic GMP and cyclic AMP signaling are key modulators of smooth muscle hypertrophy. cGMP, generated by soluble guanylate cyclase, regulates gene expression and can inhibit or promote hypertrophic responses depending on context. Phosphodiesterases (PDEs) degrade cyclic nucleotides and thus tightly control the duration and amplitude of these signals in heart and vessels. Pharmacological inhibition of PDEs can alter smooth muscle growth, making this pathway a therapeutic target.
Akt, MAP Kinase, and Apoptosis Pathways
In simple terms: Inside the cell, kinase pathways decide whether smooth muscle cells survive and grow.
The Akt and MAP kinase pathways are differentially regulated during smooth muscle hypertrophy and apoptosis. In aortic remodeling models, treatment with amlodipine modulates Akt, caspases, and MAP kinases, influencing smooth muscle cell fate. Activation of Akt promotes cell survival and growth, while MAP kinases can drive hypertrophic gene programs. The balance between these pathways determines whether smooth muscle cells undergo hypertrophy or apoptosis.
Role of LR11 and Lipoprotein Receptors
In simple terms: Certain receptors help smooth muscle cells respond to low oxygen and grow.
LR11 (also known as SorLA) is a lipoprotein receptor that contributes to hypoxia-induced pulmonary arterial smooth muscle cell proliferation and medial thickening. Deletion of LR11 attenuates these responses in mice, demonstrating its positive regulatory role in smooth muscle hypertrophy. This highlights how membrane receptors can transduce environmental cues into hypertrophic signaling.
Cell Cycle and Differentiation Control by p21Waf-1
In simple terms: Proteins that control the cell cycle also influence how big smooth muscle cells become.
p21Waf-1 (CDKN1A) is a cyclin-dependent kinase inhibitor that regulates proliferation, differentiation, and cell size in vascular smooth muscle cells. Overexpression of p21Waf-1 in these cells affects their growth and size, linking cell cycle machinery to hypertrophic responses. This suggests that positive regulation of smooth muscle hypertrophy involves coordinated changes in cell cycle regulators and differentiation markers.
Key Genes Involved in GO:1905149 positive regulation of smooth muscle hypertrophy
The following genes and proteins have been experimentally implicated in the positive regulation of smooth muscle hypertrophy, based on verified PubMed literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| B2M | Regulator of pulmonary hypertension in heart failure with preserved ejection fraction | Identified via plasma proteomics; potential biomarker and therapeutic target |
| LR11 (SORL1) | Mediates hypoxia-induced pulmonary arterial smooth muscle cell proliferation | Deletion attenuates medial thickening in mice |
| CDKN1A (p21Waf-1) | Regulates proliferation, differentiation, and cell size in vascular smooth muscle cells | Overexpression affects smooth muscle growth |
| AKT1 | Promotes cell survival and hypertrophy | Differentially regulated during aortic remodeling |
| MAPK1/3 | Drives hypertrophic gene programs | Modulated by amlodipine in SHR |
| CASP3 | Executes apoptosis | Differentially regulated in smooth muscle during remodeling |
| PDE5A | Degrades cGMP, limiting cyclic nucleotide signaling | Therapeutic target in heart and vessels |
| PDE3A | Degrades cAMP and cGMP | Modulates vascular smooth muscle tone and growth |
| GUCY1A1 | Synthesizes cGMP | Regulates gene expression in smooth muscle |
| PRKG1 | cGMP-dependent protein kinase | Mediates cGMP effects on smooth muscle |
| NR3C2 (MR) | Mediates aldosterone effects | Aldosterone antagonism in heart failure |
| EDN1 | Potent vasoconstrictor and growth factor | Contributes to vascular remodeling |
| AGTR1 | Angiotensin II receptor | Promotes smooth muscle growth in hypertension |
| TGFB1 | Pro-fibrotic and hypertrophic cytokine | Drives smooth muscle remodeling |
| MMP2 | Extracellular matrix remodeling | Facilitates vascular hypertrophy |
| MMP9 | Extracellular matrix remodeling | Facilitates vascular hypertrophy |
| COL1A1 | Collagen deposition | Contributes to vascular stiffness |
| FN1 | Fibronectin deposition | Promotes smooth muscle hypertrophy |
How Is positive regulation of smooth muscle hypertrophy Regulated?
Positive regulation of smooth muscle hypertrophy is controlled by a network of signaling pathways, including cyclic nucleotide signaling (cGMP/cAMP) and their phosphodiesterases, neurohumoral factors such as aldosterone and angiotensin II, and growth factor pathways involving Akt and MAP kinases. Proteomic regulators like B2M and lipoprotein receptors such as LR11 also modulate this process. The balance between pro-hypertrophic and pro-apoptotic signals determines the extent of smooth muscle enlargement.
positive regulation of smooth muscle hypertrophy and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| B2M | Pulmonary hypertension in HFpEF | Knockout mouse, overexpression in pulmonary smooth muscle cells |
| LR11 (SORL1) | Hypoxia-induced pulmonary arterial hypertension | LR11 knockout mouse, hypoxia exposure |
| CDKN1A (p21Waf-1) | Vascular smooth muscle hypertrophy | Overexpression in vascular smooth muscle cells |
| AKT1 | Aortic remodeling in hypertension | SHR model, amlodipine treatment |
| PDE5A | Heart failure and vascular remodeling | PDE5 inhibitor treatment in animal models |
Pulmonary Arterial Hypertension
Positive regulation of smooth muscle hypertrophy is a hallmark of pulmonary arterial hypertension, where excessive proliferation and enlargement of pulmonary arterial smooth muscle cells lead to medial thickening and increased vascular resistance. B2M has been identified as a regulator of pulmonary hypertension in heart failure with preserved ejection fraction, linking proteomic biomarkers to smooth muscle hypertrophy. LR11 deletion attenuates hypoxia-induced pulmonary arterial smooth muscle cell proliferation and medial thickening in mice, demonstrating a causal role.
Heart Failure and Vascular Remodeling
In heart failure, neurohumoral activation including aldosterone promotes vascular smooth muscle hypertrophy and remodeling. Aldosterone antagonism is a therapeutic strategy in heart failure, partly through modulation of smooth muscle growth. Cyclic nucleotide phosphodiesterases in heart and vessels represent additional targets for controlling hypertrophic remodeling.
Systemic Hypertension and Aortic Remodeling
In systemic hypertension, smooth muscle hypertrophy contributes to increased arterial wall thickness and stiffness. Studies in spontaneously hypertensive rats treated with amlodipine show differential regulation of Akt, caspases, and MAP kinases underlying smooth muscle cell apoptosis during aortic remodeling. p21Waf-1 overexpression in vascular smooth muscle cells regulates proliferation, differentiation, and cell size, highlighting cell cycle control in hypertensive remodeling.
From positive regulation of smooth muscle hypertrophy-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does B2M causally promote pulmonary smooth muscle hypertrophy? | B2M knockout mouse with hypoxia or HFpEF model |
| Does LR11 mediate hypoxia-induced pulmonary arterial smooth muscle cell proliferation? | LR11 knockout mouse exposed to hypoxia |
| Does p21Waf-1 regulate smooth muscle cell size? | p21Waf-1 overexpression in vascular smooth muscle cells |
| How does Akt signaling modulate aortic remodeling? | Akt knockout or knock-in in SHR treated with amlodipine |
| Does PDE5A inhibition reduce smooth muscle hypertrophy? | PDE5A knockout or overexpression in vascular smooth muscle cells |
| Does aldosterone receptor antagonism affect smooth muscle growth? | MR knockout or knock-in in heart failure models |
How to Study the positive regulation of smooth muscle hypertrophy Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Plasma proteomics | Circulating protein levels | Biomarker discovery in pulmonary hypertension |
| Histology and immunostaining | Vessel wall thickness, smooth muscle markers | Quantifying medial thickening in animal models |
| Western blotting | Protein expression and phosphorylation | Assessing Akt, MAPK, caspase activation |
| Kinase activity assay | Enzymatic activity | Confirming pathway activation |
| Cell culture with overexpression | Cell size, proliferation, differentiation | Testing p21Waf-1 effects |
| Cyclic nucleotide measurement | cGMP/cAMP levels | Evaluating PDE function |
| CRISPR knockout | Gene function loss | Causal testing of candidate genes |
| RNA sequencing | Transcriptomic changes | Identifying hypertrophic gene programs |
Proteomics and Biomarker Discovery
Plasma proteomics has been used to identify B2M as a regulator of pulmonary hypertension in heart failure with preserved ejection fraction, linking circulating proteins to smooth muscle hypertrophy. This approach enables unbiased discovery of novel regulators and biomarkers.
Histology and Immunostaining
Medial thickening and smooth muscle hypertrophy are assessed by histological staining and immunostaining for smooth muscle markers such as alpha-smooth muscle actin. These methods quantify vessel wall thickness and cell size in animal models.
Western Blotting and Kinase Assays
Western blotting for Akt, caspases, and MAP kinases reveals differential regulation during smooth muscle hypertrophy and apoptosis. Kinase activity assays further confirm pathway activation.
Cell Culture and Overexpression Studies
Vascular smooth muscle cells cultured in vitro are used to test the effects of gene overexpression, such as p21Waf-1, on proliferation, differentiation, and cell size. These systems allow mechanistic dissection of hypertrophic signaling.
How CRISPR Can Be Used to Study GO:1905149 positive regulation of smooth muscle hypertrophy
Knockout
CRISPR knockout of genes such as LR11 or B2M in mice or cell lines can determine whether they are required for positive regulation of smooth muscle hypertrophy. For example, LR11 deletion attenuates hypoxia-induced pulmonary arterial smooth muscle cell proliferation and medial thickening.
Point Mutation
Point mutations can be introduced to mimic or disrupt phosphorylation sites or catalytic residues in kinases like Akt or PDEs, testing their role in smooth muscle hypertrophy. This allows precise structure-function analysis.
Knock-in
Knock-in of reporter tags or human disease variants into endogenous loci enables tracking of protein expression and function in smooth muscle hypertrophy models. For example, tagging p21Waf-1 can reveal its dynamic regulation.
Overexpression
CRISPR activation or transgenic overexpression of candidate genes such as p21Waf-1 or B2M can drive smooth muscle hypertrophy in vitro and in vivo, confirming sufficiency. Overexpression models are useful for testing therapeutic interventions.
How EDITGENE Supports positive regulation of smooth muscle hypertrophy Research
Researchers studying positive regulation of smooth muscle hypertrophy-related genes often need to determine whether a candidate gene is causally involved in driving smooth muscle cell enlargement or whether it is merely a bystander. CRISPR-based models provide the gold standard for such causal inference, enabling precise genetic manipulation in relevant cell types and animal models.
Contact EDITGENE today to design your custom CRISPR model for positive regulation of smooth muscle hypertrophy research.
Frequently Asked Questions About positive regulation of smooth muscle hypertrophy
What is GO:1905149?
GO:1905149 is the Gene Ontology term for positive regulation of smooth muscle hypertrophy, defined as any process that activates or increases the frequency, rate or extent of smooth muscle hypertrophy.
What genes are involved in positive regulation of smooth muscle hypertrophy?
Key genes include B2M, LR11 (SORL1), CDKN1A (p21Waf-1), AKT1, MAPK1/3, PDE5A, and others involved in cyclic nucleotide and growth factor signaling.
How is smooth muscle hypertrophy regulated?
It is regulated by cyclic nucleotide signaling (cGMP/cAMP), phosphodiesterases, neurohumoral factors like aldosterone, and growth factor pathways including Akt and MAP kinases.
What diseases are associated with positive regulation of smooth muscle hypertrophy?
Pulmonary arterial hypertension, heart failure with preserved ejection fraction, systemic hypertension, and aortic remodeling are associated with this process.
What is the role of B2M in smooth muscle hypertrophy?
B2M has been identified as a regulator of pulmonary hypertension in heart failure with preserved ejection fraction, linking it to smooth muscle hypertrophy.
How does LR11 affect smooth muscle hypertrophy?
LR11 deletion attenuates hypoxia-induced pulmonary arterial smooth muscle cell proliferation and medial thickening in mice, indicating a positive regulatory role.
What experimental models are used to study positive regulation of smooth muscle hypertrophy?
Models include knockout mice, overexpression cell lines, and pharmacological interventions such as amlodipine or PDE inhibitors.
What is the role of p21Waf-1 in smooth muscle cells?
p21Waf-1 overexpression regulates proliferation, differentiation, and cell size in vascular smooth muscle cells.
How do phosphodiesterases affect smooth muscle hypertrophy?
Phosphodiesterases degrade cyclic nucleotides and thus modulate smooth muscle growth; PDE inhibitors are therapeutic candidates.
Can CRISPR be used to study smooth muscle hypertrophy?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models enable causal testing of genes in smooth muscle hypertrophy.
Conclusion
GO:1905149, positive regulation of smooth muscle hypertrophy, is a biologically and clinically significant process driven by a complex network of signaling pathways and genes. Key regulators such as B2M, LR11, and p21Waf-1 have been experimentally linked to smooth muscle hypertrophy in cardiovascular disease models. Understanding these mechanisms offers opportunities for therapeutic intervention in pulmonary hypertension, heart failure, and systemic hypertension. CRISPR-based models and bioinformatics tools are essential for dissecting the causal roles of candidate genes and accelerating translational research.
References
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- 2. Sethi R et al.. 2024. Evidence for Aldosterone Antagonism in Heart Failure.. Card Fail Rev 10:e15 PMID: 39588014
- 3. Pilz RB et al.. 2003. Regulation of gene expression by cyclic GMP.. Circ Res 93(11):1034-46 PMID: 14645134
- 4. Kato S et al.. 1999. Overexpression of p21Waf-1 in vascular smooth muscle cells: regulation of proliferation, differentiation, and cell size.. Exp Mol Pathol 66(1):39-52 PMID: 10331963
- 5. Duguay D et al.. 2007. Differential regulation of Akt, caspases and MAP kinases underlies smooth muscle cell apoptosis during aortic remodelling in SHR treated with amlodipine.. Br J Pharmacol 151(8):1315-23 PMID: 17592516
- 7. Jiang L et al.. 2016. Deletion of LR11 Attenuates Hypoxia-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation With Medial Thickening in Mice.. Arterioscler Thromb Vasc Biol 36(9):1972-9 PMID: 27493099
- 8. Bobin P et al.. 2016. Cyclic nucleotide phosphodiesterases in heart and vessels: A therapeutic perspective.. Arch Cardiovasc Dis 109(6-7):431-43 PMID: 27184830
