GO:1905111 positive regulation of pulmonary blood vessel remodeling: Signaling Drivers, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1905111 describes any process that activates or increases the frequency, rate or extent of pulmonary blood vessel remodeling, a biological process central to pulmonary hypertension and other vascular diseases.
• Pulmonary blood vessel remodeling involves endothelial dysfunction, smooth muscle cell phenotypic switching, extracellular matrix deposition, and pericyte activation.
• Metabolic reprogramming, including LDHA-mediated lactate generation and hexokinase 2-driven glycolysis, actively promotes pulmonary vascular remodeling.
• Epigenetic regulators such as METTL7B and the m6A-driven miR-143/145-KLF4 circuit modulate the phenotypic switch of pulmonary artery smooth muscle cells.
• Proteoglycan deposition and macrophage-derived factors like CARD9 and lipocalin 2 contribute to vascular wall remodeling and cardiac injury.
• CRISPR knockout, point mutation, knock-in, and overexpression models are essential for causally testing candidate genes in pulmonary blood vessel remodeling.
Description
Pulmonary blood vessel remodeling is a pathological process in which the structure of pulmonary arteries and arterioles is progressively altered, leading to increased vascular resistance and right heart failure. The Gene Ontology term GO:1905111, positive regulation of pulmonary blood vessel remodeling, captures any molecular or cellular event that activates or increases the frequency, rate, or extent of this remodeling process. This term is critical for researchers studying pulmonary hypertension, where vascular remodeling is a hallmark, as well as other cardiopulmonary diseases. Understanding the positive regulators of pulmonary blood vessel remodeling provides mechanistic insight into disease progression and identifies potential therapeutic targets. Recent studies have highlighted the roles of metabolic enzymes such as LDHA and hexokinase 2 in driving vascular remodeling through lactate production and pericyte contractility. Additionally, epigenetic modifiers like METTL7B and the m6A reader machinery regulate smooth muscle cell phenotypic switching, a key step in remodeling. Extracellular matrix components, including proteoglycans, and inflammatory mediators such as CARD9 and lipocalin 2 further contribute to the remodeling milieu. This article synthesizes current knowledge on GO:1905111, covering its definition, mechanisms, key genes, disease relevance, and research methodologies, with a focus on CRISPR-based approaches for functional validation.
positive regulation of pulmonary blood vessel remodeling At A Glance
| GO ID | GO:1905111 |
|---|---|
| GO term | positive regulation of pulmonary blood vessel remodeling |
| Ontology | biological_process |
| Synonym | activation of pulmonary blood vessel remodeling; positive regulation of pulmonary blood vessel remodelling; up regulation of pulmonary blood vessel remodeling; up-regulation of pulmonary blood vessel remodeling; upregulation of pulmonary blood vessel remodeling |
| Major function | Activates or increases the frequency, rate or extent of pulmonary blood vessel remodeling |
| Related processes | Pulmonary hypertension, vascular smooth muscle cell phenotypic switching, endothelial dysfunction, extracellular matrix remodeling |
| Key regulators | LDHA, hexokinase 2, METTL7B, miR-143/145-KLF4 circuit, CARD9, proteoglycans |
| Disease relevance | Pulmonary arterial hypertension, systemic sclerosis-associated vasculopathy, myocardial infarction-induced cardiac injury |
What Is GO:1905111?
GO:1905111, positive regulation of pulmonary blood vessel remodeling, is defined as any process that activates or increases the frequency, rate or extent of pulmonary blood vessel remodeling. In other words, it encompasses molecular signals, cellular behaviors, and environmental cues that promote structural changes in pulmonary blood vessels, such as thickening of the vessel wall, increased smooth muscle cell proliferation, endothelial dysfunction, and extracellular matrix deposition. This term is a child of positive regulation of blood vessel remodeling and is specific to the pulmonary circulation.
Why Is positive regulation of pulmonary blood vessel remodeling Important in Cell Biology?
GO:1905111 is important because pulmonary blood vessel remodeling is a central pathological mechanism in pulmonary hypertension and other cardiopulmonary disorders, and positive regulators of this process represent potential therapeutic targets. Research has shown that metabolic, epigenetic, and inflammatory pathways converge to drive remodeling, and understanding these positive regulatory mechanisms can inform the development of interventions to halt or reverse disease progression.
• Pulmonary blood vessel remodeling is a hallmark of pulmonary arterial hypertension, a disease with high morbidity and mortality.
• Positive regulators such as LDHA-mediated lactate production directly promote vascular remodeling and are potential drug targets.
• Hexokinase 2-driven glycolysis in pericytes activates contractility, leading to blood vessel abnormalities.
• Epigenetic regulation by METTL7B and m6A modifications modulates hypertension and vascular remodeling.
• Macrophage CARD9 signaling mediates cardiac injury and may influence pulmonary vascular remodeling through lipocalin 2.
• Proteoglycan deposition in the pulmonary arterial wall is altered in pulmonary hypertension, contributing to remodeling.
• Soluble ST2 has been identified as a biomarker for acute aortic dissection, highlighting the broader relevance of vascular remodeling biomarkers.
• Antimicrobial peptide LL-37 contributes to tissue fibrosis and vasculopathy in systemic sclerosis, a disease with pulmonary vascular involvement.
• Understanding positive regulation can guide CRISPR-based screens to identify novel therapeutic targets.
• Modeling GO:1905111 in vitro and in vivo enables preclinical testing of gene-editing therapies.
What Happens During positive regulation of pulmonary blood vessel remodeling?
Metabolic Reprogramming and Lactate Signaling
In simple terms: Cells in the pulmonary vessel wall switch their energy production to produce more lactate, which signals them to remodel.
A key initiating event in positive regulation of pulmonary blood vessel remodeling is the shift in cellular metabolism toward aerobic glycolysis. LDHA-mediated lactate generation promotes pulmonary vascular remodeling in pulmonary hypertension, as lactate serves as a signaling molecule that activates fibroblasts and smooth muscle cells. Similarly, hexokinase 2-driven glycolysis in pericytes activates their contractility, leading to tumor blood vessel abnormalities, a process that parallels pulmonary vascular remodeling. These metabolic changes increase the frequency and extent of remodeling by providing energy and biosynthetic precursors for cell proliferation and matrix deposition.
Epigenetic Regulation of Smooth Muscle Cell Phenotypic Switching
In simple terms: Chemical tags on DNA and RNA control whether smooth muscle cells change into a disease-causing state.
Pulmonary artery smooth muscle cells (PASMCs) undergo a phenotypic switch from a contractile to a synthetic, proliferative state during remodeling. The N6-methyladenosine (m6A)-driven miR-143/145-KLF4 circuit orchestrates this switch, with METTL7B and other m6A regulators modulating the process. METTL7B mitigates hypertension and vascular remodeling, indicating that its positive regulation involves fine-tuning of epigenetic marks. This epigenetic control increases the rate of remodeling by altering gene expression programs that govern cell proliferation, migration, and matrix production.
Inflammatory and Immune Cell Contributions
In simple terms: Immune cells release signals that make blood vessels remodel.
Macrophages and other immune cells infiltrate the pulmonary vessel wall and release factors that promote remodeling. Macrophage CARD9 mediates cardiac injury following myocardial infarction through regulation of lipocalin 2 expression, and similar mechanisms may operate in pulmonary vasculature. The antimicrobial peptide LL-37 contributes to tissue fibrosis and vasculopathy in systemic sclerosis, a disease often complicated by pulmonary vascular remodeling. These inflammatory signals increase the frequency and extent of remodeling by stimulating cell proliferation and extracellular matrix synthesis.
Extracellular Matrix Remodeling and Proteoglycan Deposition
In simple terms: The scaffold around blood vessel cells changes, making the vessel wall thicker and stiffer.
Proteoglycans are major components of the extracellular matrix in the pulmonary arterial wall, and their expression and deposition are comprehensively altered in pulmonary hypertension. This matrix remodeling increases the extent of pulmonary blood vessel remodeling by providing a scaffold for cell migration and proliferation, and by sequestering growth factors. The dynamic changes in proteoglycan composition contribute to the structural and functional changes characteristic of GO:1905111.
Biomarker and Systemic Signals
In simple terms: Molecules in the blood can indicate how much blood vessels are remodeling.
Soluble ST2 has been identified as a novel biomarker for acute aortic dissection, reflecting the magnitude of vascular remodeling. Although this study focused on aortic dissection, it highlights the concept that circulating factors can mirror the intensity of positive regulation of blood vessel remodeling. In the pulmonary context, similar biomarkers may help monitor disease activity and response to therapies targeting GO:1905111.
Key Genes Involved in GO:1905111 positive regulation of pulmonary blood vessel remodeling
The following genes and proteins have been experimentally implicated in positive regulation of pulmonary blood vessel remodeling or related vascular remodeling processes.
| Gene | Major Role | Research Relevance |
|---|---|---|
| LDHA | Lactate generation; promotes pulmonary vascular remodeling | Target for metabolic intervention in pulmonary hypertension |
| HK2 | Hexokinase 2-driven glycolysis in pericytes; activates contractility | Potential target for normalizing tumor and pulmonary vessel abnormalities |
| CARD9 | Macrophage signaling; mediates cardiac injury via lipocalin 2 | Links inflammation to vascular remodeling |
| METTL7B | Mitigates hypertension and vascular remodeling | Epigenetic regulator with protective role |
| KLF4 | Transcription factor in miR-143/145 circuit; controls PASMC phenotypic switch | Key node in epigenetic regulation of remodeling |
| miR-143/145 | MicroRNAs regulated by m6A; modulate KLF4 expression | Epigenetic circuit controlling smooth muscle phenotype |
| Proteoglycans (various) | Extracellular matrix components; altered in pulmonary hypertension | Matrix remodeling and biomarker potential |
| ST2 | Soluble form is a biomarker for acute aortic dissection | Systemic marker of vascular remodeling |
| LL-37 | Antimicrobial peptide; contributes to fibrosis and vasculopathy | Inflammatory mediator in systemic sclerosis |
| Lipocalin 2 | Downstream of CARD9; mediates cardiac injury | Potential mediator of vascular remodeling |
| m6A writers/erasers | Regulate RNA methylation; affect miR-143/145-KLF4 circuit | Epigenetic modifiers of remodeling |
| Glycolytic enzymes | Support metabolic reprogramming in vascular cells | Metabolic targets for remodeling |
| Inflammatory cytokines | Recruit immune cells; promote proliferation | Inflammatory drivers of remodeling |
| Growth factors (e.g., PDGF, FGF) | Stimulate smooth muscle cell proliferation | Classic remodeling mediators (implied by) |
| Matrix metalloproteinases | Degrade and remodel extracellular matrix | Enzymes facilitating structural changes |
| Endothelial adhesion molecules | Mediate immune cell infiltration | Inflammatory component of remodeling |
| Hypoxia-inducible factors | Sense oxygen; drive metabolic and proliferative responses | Upstream regulators of remodeling |
How Is positive regulation of pulmonary blood vessel remodeling Regulated?
Positive regulation of pulmonary blood vessel remodeling is controlled by a complex network of metabolic, epigenetic, and inflammatory signals. LDHA-mediated lactate production acts as a positive feedback signal, promoting further remodeling. Hexokinase 2-driven glycolysis in pericytes enhances contractility, contributing to vessel abnormalities. Epigenetic regulators such as METTL7B and the m6A machinery modulate the miR-143/145-KLF4 circuit, influencing smooth muscle cell phenotypic switching. Inflammatory mediators like CARD9 and LL-37 amplify remodeling through cytokine and matrix interactions. Proteoglycan deposition provides structural support and modulates growth factor availability. These pathways converge to increase the frequency, rate, and extent of pulmonary blood vessel remodeling.
positive regulation of pulmonary blood vessel remodeling and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| LDHA | Pulmonary hypertension | LDHA knockout or overexpression in PASMCs; hypoxia-induced PH mouse model |
| METTL7B | Hypertension and vascular remodeling | METTL7B knockout mice; vascular smooth muscle cell-specific deletion |
| KLF4 | Pulmonary arterial hypertension; PASMC phenotypic switch | KLF4 knockout or knock-in in PASMCs; m6A modification studies |
| CARD9 | Myocardial infarction-induced cardiac injury | CARD9 knockout mice; macrophage-specific deletion |
| Proteoglycans | Pulmonary hypertension; matrix remodeling | Genetic models altering proteoglycan expression; pulmonary artery smooth muscle cells |
Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is characterized by excessive pulmonary blood vessel remodeling, leading to increased vascular resistance and right heart failure. Positive regulators such as LDHA and the m6A-driven miR-143/145-KLF4 circuit are directly implicated in PAH pathogenesis. METTL7B has been shown to mitigate hypertension and vascular remodeling, suggesting a protective role that when lost, enhances remodeling. Proteoglycan deposition is altered in PAH, contributing to vessel wall thickening. Targeting these positive regulators may offer therapeutic benefit.
Systemic Sclerosis-Associated Vasculopathy
Systemic sclerosis is an autoimmune disease characterized by fibrosis and vasculopathy, often affecting the pulmonary circulation. The antimicrobial peptide LL-37 contributes to tissue fibrosis and vasculopathy in systemic sclerosis, linking inflammation to vascular remodeling. This suggests that LL-37 may be a positive regulator of pulmonary blood vessel remodeling in the context of autoimmune disease.
Cardiac Injury and Remodeling
Macrophage CARD9 mediates cardiac injury following myocardial infarction through regulation of lipocalin 2 expression. Although this study focuses on the heart, the same inflammatory pathways may influence pulmonary vascular remodeling, especially in the setting of heart failure, which can lead to pulmonary hypertension. Soluble ST2, a biomarker for acute aortic dissection, reflects the magnitude of vascular remodeling and may also be relevant in pulmonary vascular disease.
Tumor Angiogenesis and Vascular Abnormalities
Hexokinase 2-driven glycolysis in pericytes activates their contractility, leading to tumor blood vessel abnormalities. This mechanism parallels pulmonary blood vessel remodeling, as pericytes play a role in both contexts. Understanding how metabolic reprogramming in pericytes drives vascular abnormalities may provide insights into positive regulation of pulmonary blood vessel remodeling.
From positive regulation of pulmonary blood vessel remodeling-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does LDHA-mediated lactate production causally promote pulmonary vascular remodeling? | LDHA knockout mice or PASMC-specific LDHA knockout; lactate supplementation |
| What is the role of METTL7B in hypertension and vascular remodeling? | METTL7B knockout and transgenic overexpression mice; vascular smooth muscle cell-specific models |
| How does the m6A-driven miR-143/145-KLF4 circuit regulate PASMC phenotypic switching? | KLF4 knock-in with mutated m6A sites; miR-143/145 knockout mice |
| Does CARD9 signaling in macrophages contribute to pulmonary vascular remodeling? | Macrophage-specific CARD9 knockout mice; bone marrow chimeras |
| What is the impact of proteoglycan deposition on pulmonary arterial wall remodeling? | Knock-in mice expressing tagged proteoglycans; inducible overexpression in smooth muscle cells |
| Can hexokinase 2 inhibition reverse pericyte-mediated vascular abnormalities? | HK2 knockout or point mutation (catalytic dead) in pericytes; pericyte-specific Cre lines |
How to Study the positive regulation of pulmonary blood vessel remodeling Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Global gene expression changes | Identify transcriptional programs driving remodeling |
| m6A-seq | RNA methylation sites | Map m6A modifications in PASMCs |
| Seahorse assay | Glycolytic rate and oxidative phosphorylation | Assess metabolic reprogramming |
| Lactate assay | Lactate production | Quantify LDHA activity |
| Immunohistochemistry | Protein localization and abundance in tissue | Visualize proteoglycans and remodeling markers |
| Western blot | Protein expression and phosphorylation | Validate signaling changes |
| CRISPR screen | Gene essentiality or activation in remodeling | Discover novel positive regulators |
| Proximity ligation assay | Protein-protein interactions | Study complex formation in remodeling pathways |
Transcriptomic and Epigenomic Profiling
RNA-seq and m6A-seq can identify global changes in gene expression and RNA methylation during pulmonary blood vessel remodeling. For example, the m6A-driven miR-143/145-KLF4 circuit was elucidated using such approaches. These methods help pinpoint positive regulators and their downstream targets.
Metabolic Assays
Seahorse extracellular flux analysis and lactate measurements can assess glycolytic activity and lactate production, key features of metabolic reprogramming in remodeling. These assays quantify the contribution of LDHA and hexokinase 2 to the positive regulation of remodeling.
Histological and Imaging Techniques
Immunohistochemistry, immunofluorescence, and electron microscopy can visualize vessel wall thickening, proteoglycan deposition, and cellular changes in pulmonary arteries. These methods provide spatial and structural information about the extent of remodeling.
CRISPR-Based Functional Genomics
CRISPR knockout, activation, and interference screens enable unbiased discovery of positive regulators of pulmonary blood vessel remodeling. Libraries targeting epigenetic modifiers, metabolic enzymes, and signaling molecules can be applied in primary PASMCs or endothelial cells under remodeling-inducing conditions.
How CRISPR Can Be Used to Study GO:1905111 positive regulation of pulmonary blood vessel remodeling
Knockout
CRISPR knockout of candidate positive regulators such as LDHA, METTL7B, or KLF4 in pulmonary artery smooth muscle cells or endothelial cells can determine whether their loss reduces the frequency or extent of remodeling. In vivo knockout mice, including conditional models, allow assessment of remodeling in hypoxia- or monocrotaline-induced pulmonary hypertension.
Point Mutation
Introducing point mutations that abrogate catalytic activity or specific post-translational modification sites (e.g., in LDHA or METTL7B) can dissect the molecular mechanisms by which these genes positively regulate remodeling. For example, a catalytically dead LDHA mutant can test whether lactate production is required.
Knock-in
Knock-in of tagged versions of proteins (e.g., HA-tagged METTL7B or KLF4) enables chromatin immunoprecipitation and proteomic studies to identify interaction partners and DNA binding sites. Knock-in of disease-associated mutations can model human variants that enhance remodeling.
Overexpression
Overexpression of candidate positive regulators such as LDHA, hexokinase 2, or LL-37 in pulmonary vascular cells or transgenic mice can test sufficiency for inducing remodeling. This approach helps establish causality and identify downstream effectors.
How EDITGENE Supports positive regulation of pulmonary blood vessel remodeling Research
Researchers studying positive regulation of pulmonary blood vessel remodeling-related genes often need to determine whether a candidate gene is causally involved in the process or merely a bystander. EDITGENE provides a comprehensive suite of CRISPR-based services to enable such functional validation, from knockout to precise point mutations and knock-in models, as well as high-throughput library screening and bioinformatics support.
Contact EDITGENE today to design your custom CRISPR model for positive regulation of pulmonary blood vessel remodeling research.
Frequently Asked Questions About positive regulation of pulmonary blood vessel remodeling
What is GO:1905111?
GO:1905111 is a Gene Ontology biological process term defined as any process that activates or increases the frequency, rate or extent of pulmonary blood vessel remodeling.
What genes are involved in positive regulation of pulmonary blood vessel remodeling?
Key genes include LDHA, HK2, METTL7B, KLF4, miR-143/145, CARD9, and various proteoglycans, as shown in recent studies.
How does LDHA promote pulmonary vascular remodeling?
LDHA-mediated lactate generation promotes pulmonary vascular remodeling by providing lactate as a signaling molecule that activates fibroblasts and smooth muscle cells.
What is the role of METTL7B in vascular remodeling?
METTL7B mitigates hypertension and vascular remodeling, suggesting it acts as a negative regulator or protective factor.
How is the miR-143/145-KLF4 circuit involved in remodeling?
The m6A-driven miR-143/145-KLF4 circuit orchestrates the phenotypic switch of pulmonary artery smooth muscle cells, a key step in remodeling.
What experimental models are used to study pulmonary blood vessel remodeling?
Common models include knockout mice, PASMC-specific conditional knockouts, hypoxia-induced pulmonary hypertension models, and CRISPR screens in primary vascular cells.
Can CRISPR be used to study positive regulators of pulmonary blood vessel remodeling?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression approaches enable causal testing of candidate genes in remodeling.
What diseases are associated with GO:1905111?
Pulmonary arterial hypertension, systemic sclerosis-associated vasculopathy, and cardiac injury following myocardial infarction are associated with this process.
What is the role of proteoglycans in pulmonary blood vessel remodeling?
Proteoglycans are extracellular matrix components whose expression and deposition are altered in pulmonary hypertension, contributing to vessel wall remodeling.
How can I model positive regulation of pulmonary blood vessel remodeling in the lab?
You can use CRISPR-engineered cell lines and animal models, metabolic assays, and histological techniques to study this process.
Conclusion
GO:1905111, positive regulation of pulmonary blood vessel remodeling, encompasses a complex interplay of metabolic, epigenetic, and inflammatory signals that drive structural changes in the pulmonary vasculature. Key regulators such as LDHA, hexokinase 2, METTL7B, and the miR-143/145-KLF4 circuit have been experimentally linked to this process, offering potential therapeutic targets for pulmonary hypertension and related diseases. CRISPR-based functional genomics provides a powerful approach to identify and validate novel positive regulators, and EDITGENE offers comprehensive services to support such research. Continued investigation into the mechanisms of GO:1905111 will likely yield new strategies to prevent or reverse pulmonary vascular remodeling.
References
- 1. Wu D et al.. 2024. Lactate dehydrogenase A (LDHA)-mediated lactate generation promotes pulmonary vascular remodeling in pulmonary hypertension.. J Transl Med 22(1):738 PMID: 39103838
- 2. Meng YM et al.. 2021. Hexokinase 2-driven glycolysis in pericytes activates their contractility leading to tumor blood vessel abnormalities.. Nat Commun 12(1):6011 PMID: 34650057
- 3. Liu Y et al.. 2023. Macrophage CARD9 mediates cardiac injury following myocardial infarction through regulation of lipocalin 2 expression.. Signal Transduct Target Ther 8(1):394 PMID: 37828006
- 4. Chen Z et al.. 2026. METTL7B Mitigates Hypertension and Vascular Remodeling.. Circulation PMID: 42639676
- 5. Wang Y et al.. 2018. Magnitude of Soluble ST2 as a Novel Biomarker for Acute Aortic Dissection.. Circulation 137(3):259-269 PMID: 29146682
- 6. Takahashi T et al.. 2016. A potential contribution of antimicrobial peptide LL-37 to tissue fibrosis and vasculopathy in systemic sclerosis.. Br J Dermatol 175(6):1195-1203 PMID: 27105895
- 7. Kang K et al.. 2024. N6-methyladenosine-driven miR-143/145-KLF4 circuit orchestrates the phenotypic switch of pulmonary artery smooth muscle cells.. Cell Mol Life Sci 81(1):256 PMID: 38866991
- 8. Mutgan AC et al.. 2024. A comprehensive map of proteoglycan expression and deposition in the pulmonary arterial wall in health and pulmonary hypertension.. Am J Physiol Lung Cell Mol Physiol 327(2):L173-L188 PMID: 38771138
