GO:1903588 negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1903588 describes the biological process that stops, prevents, or reduces endothelial cell proliferation specifically during sprouting angiogenesis, a key control point in new blood vessel formation.
• This process is distinct from general negative regulation of endothelial proliferation because it is spatially and temporally restricted to the sprouting phase of angiogenesis.
• Key molecular brakes include microRNAs such as miR-1-3p and miR-93-5p, which modulate endothelial growth factor signaling and cytoskeletal dynamics.
• Dysregulation of this process contributes to pathological angiogenesis in abdominal aortic aneurysm, tumor growth, and other vascular disorders.
• Experimental models for studying GO:1903588 include endothelial cell sprouting assays, knockout and overexpression cell lines, and CRISPR-based screens.
• Therapeutic targeting of this process may offer strategies to normalize or inhibit aberrant angiogenesis in cancer and vascular disease.
Description
Sprouting angiogenesis is the process by which new blood vessels emerge from pre-existing vasculature, and it is tightly controlled by a balance of pro- and anti-angiogenic signals. GO:1903588, negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis, captures the specific biological process that restrains endothelial cell division during this sprouting phase. This term is essential for understanding how vascular growth is limited to appropriate times and locations, preventing excessive or insufficient vessel formation. Researchers study GO:1903588 to identify molecular brakes that can be harnessed to treat angiogenesis-dependent diseases such as cancer, where tumor growth relies on new vessel formation. The process involves microRNAs, signaling kinases, and transcription factors that collectively suppress endothelial proliferation. By focusing on this GO term, scientists can dissect the precise regulatory nodes that control vascular sprouting and develop targeted interventions.
negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis At A Glance
| GO ID | GO:1903588 |
|---|---|
| GO term | negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis |
| Ontology | biological_process |
| Synonym | inhibition of blood vessel endothelial cell proliferation during sprouting angiogenesis; downregulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis |
| Major function | Suppression of endothelial cell proliferation specifically during sprouting angiogenesis, controlling vascular growth |
| Related processes | Angiogenesis, endothelial cell cycle regulation, vascular sprouting |
| Key regulators | miR-1-3p, miR-93-5p, EPLIN, JNK, Egr-1 |
| Disease relevance | Abdominal aortic aneurysm, tumor angiogenesis, vascular disorders |
What Is GO:1903588?
GO:1903588 refers to any process that stops, prevents, or reduces the frequency, rate, or extent of blood vessel endothelial cell proliferation specifically during sprouting angiogenesis. In other words, it is the set of molecular events that put the brakes on endothelial cell division when new capillary sprouts are forming, ensuring that vessel growth is balanced and properly timed.
Why Is negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis Important in Cell Biology?
GO:1903588 is critical because uncontrolled endothelial proliferation during sprouting angiogenesis drives pathological conditions such as tumor growth, where new blood vessels supply nutrients to expanding malignancies. Conversely, insufficient negative regulation can lead to vascular malformations or aneurysm progression, as seen in abdominal aortic aneurysm where circulating miR-1-3p levels are altered. Understanding this process provides a framework for developing therapies that either inhibit or promote angiogenesis in a context-dependent manner.
• Controls the balance between vessel growth and quiescence, preventing excessive angiogenesis.
• Dysregulation is linked to abdominal aortic aneurysm, where miR-1-3p serves as a potential biomarker.
• Tumor angiogenesis depends on escaping negative regulation, making this process a therapeutic target.
• MicroRNAs such as miR-93-5p modulate endothelial proliferation by targeting EPLIN, affecting sprouting.
• JNK signaling acts as a positive regulator of angiogenic potential, indirectly influencing negative feedback loops.
• Egr-1 sustained expression blocks angiogenesis and tumor growth, highlighting negative regulatory mechanisms.
• Provides mechanistic insights for developing anti-angiogenic drugs in cancer.
• Helps explain how endothelial cells switch from proliferative to quiescent states during vascular remodeling.
• Offers biomarkers like miR-1-3p for diagnosing vascular diseases.
• Guides CRISPR-based screens to identify novel negative regulators of sprouting angiogenesis.
What Happens During negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis?
Initiation of negative regulatory signals
In simple terms: The process begins when signals tell endothelial cells to stop dividing during sprouting.
Negative regulation of endothelial proliferation during sprouting angiogenesis is initiated by extracellular cues such as microRNAs and growth factor imbalances. For example, miR-1-3p is associated with abdominal aortic aneurysm and may influence endothelial proliferation. Similarly, miR-93-5p down-regulates EPLIN, which enhances growth and angiogenesis, indicating that its suppression could relieve negative regulation. These signals set the stage for halting cell cycle progression in sprouting endothelial cells.
Signal transduction to cell cycle machinery
In simple terms: Signals are relayed inside the cell to the machinery that controls cell division.
Once negative regulatory cues are received, intracellular pathways such as JNK signaling modulate angiogenic potential. JNK acts as a positive regulator of angiogenic potential in endothelial cells, suggesting that its inhibition may contribute to negative regulation. Additionally, sustained expression of early growth response protein-1 (Egr-1) blocks angiogenesis and tumor growth, likely by interfering with proliferative signaling. These pathways converge on cell cycle regulators to reduce proliferation.
Inhibition of endothelial cell proliferation
In simple terms: The cell cycle is slowed or stopped, preventing endothelial cells from multiplying.
The ultimate outcome of GO:1903588 is reduced frequency, rate, or extent of endothelial cell proliferation specifically during sprouting angiogenesis. This involves down-regulation of cyclins and other proliferation markers, although specific mechanisms may vary by context. The process ensures that sprouting vessels do not overgrow and maintains vascular homeostasis.
Resolution and maintenance of quiescence
In simple terms: After proliferation is stopped, endothelial cells remain quiet until new growth signals appear.
Following negative regulation, endothelial cells enter a quiescent state. Sustained expression of Egr-1 has been shown to block angiogenesis and tumor growth, indicating a lasting effect on vascular quiescence. This resolution phase is crucial for preventing pathological angiogenesis and is often disrupted in diseases such as abdominal aortic aneurysm.
Key Genes Involved in GO:1903588 negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis
The following genes and non-coding RNAs have been implicated in the negative regulation of blood vessel endothelial cell proliferation during sprouting angiogenesis, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| MIR1-3P | MicroRNA associated with abdominal aortic aneurysm; potential circulating biomarker | May modulate endothelial proliferation and serve as a diagnostic marker |
| MIR93-5P | Enhances growth and angiogenesis by down-regulating EPLIN | Its inhibition could relieve negative regulation of proliferation |
| EPLIN | Actin-associated protein; target of miR-93-5p | Down-regulation enhances endothelial growth and angiogenesis |
| MAPK8 (JNK) | Positive regulator of angiogenic potential in endothelial cells | Inhibition may contribute to negative regulation of proliferation |
| EGR1 | Early growth response protein-1; blocks angiogenesis and tumor growth | Sustained expression suppresses endothelial proliferation |
| VEGFA | Key pro-angiogenic growth factor | Indirectly opposed by negative regulatory mechanisms |
| CDKN1A (p21) | Cyclin-dependent kinase inhibitor | Potential mediator of cell cycle arrest in endothelial cells |
| CDKN1B (p27) | Cyclin-dependent kinase inhibitor | May contribute to reduced proliferation during sprouting |
| TP53 | Tumor suppressor; regulates cell cycle and apoptosis | Can influence endothelial proliferation under stress |
| HIF1A | Hypoxia-inducible factor; drives angiogenesis | Its activity may be counteracted by negative regulators |
| NOTCH1 | Receptor involved in vascular development | Notch signaling can suppress endothelial proliferation |
| DLL4 | Notch ligand; regulates sprouting angiogenesis | Inhibits excessive sprouting through Notch activation |
| PECAM1 (CD31) | Endothelial cell adhesion molecule | Marker of endothelial cells; may be affected during proliferation changes |
| CDH5 (VE-cadherin) | Endothelial adherens junction protein | Maintains vascular integrity; linked to proliferation control |
| KDR (VEGFR2) | Vascular endothelial growth factor receptor 2 | Mediates pro-angiogenic signals opposed by negative regulators |
| FLT1 (VEGFR1) | Vascular endothelial growth factor receptor 1 | Can sequester VEGF and negatively regulate angiogenesis |
How Is negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis Regulated?
The process of negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis is itself regulated by microRNAs, signaling kinases, and transcription factors. For instance, miR-1-3p levels are altered in abdominal aortic aneurysm and may influence endothelial proliferation. miR-93-5p targets EPLIN to enhance angiogenesis, implying that its down-regulation could promote negative regulation. JNK signaling acts as a positive regulator of angiogenic potential, so its inhibition may enhance negative regulation. Sustained Egr-1 expression blocks angiogenesis, demonstrating a regulatory role for this transcription factor. These regulators form a network that fine-tunes endothelial proliferation during sprouting.
negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| MIR1-3P | Abdominal aortic aneurysm | Knockout or overexpression in endothelial cells; circulating biomarker studies |
| MIR93-5P | Tumor angiogenesis | Knockdown and overexpression in HUVECs; xenograft models |
| MAPK8 (JNK) | Vascular disorders | CRISPR knockout in endothelial cells; sprouting assays |
| EGR1 | Cancer, tumor growth | Inducible overexpression in endothelial cells; tumor models |
| EPLIN | Angiogenesis regulation | Point mutation or knockout to study cytoskeletal dynamics |
Abdominal Aortic Aneurysm
Abdominal aortic aneurysm (AAA) is characterized by weakening of the aortic wall, often involving altered angiogenesis. Serum miR-1-3p has been identified as a potential circulating biomarker for AAA, suggesting that dysregulation of microRNAs involved in negative regulation of endothelial proliferation may contribute to disease pathogenesis. The exact mechanisms linking GO:1903588 to AAA remain under investigation, but the association highlights the clinical relevance of this process.
Cancer and Tumor Angiogenesis
Tumor growth depends on angiogenesis to supply oxygen and nutrients. Negative regulation of endothelial proliferation during sprouting is often circumvented in tumors. Sustained expression of Egr-1 blocks angiogenesis and tumor growth, demonstrating that restoring negative regulation can inhibit tumor progression. Similarly, miR-93-5p enhances angiogenesis by down-regulating EPLIN, indicating that loss of negative regulation promotes tumor vascularization. Targeting these pathways is a promising anti-cancer strategy.
Vascular Disorders
Beyond AAA and cancer, dysregulation of sprouting angiogenesis contributes to various vascular disorders. JNK signaling, which positively regulates angiogenic potential, may be altered in conditions of excessive or insufficient vessel growth. Understanding how negative regulation is disrupted could lead to new therapies for ischemic diseases and vascular malformations.
From negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of a candidate gene enhance endothelial proliferation during sprouting? | CRISPR knockout in HUVECs or primary endothelial cells |
| Does a specific point mutation in a regulator alter its function? | Point mutation knock-in via CRISPR in endothelial cell lines |
| Does overexpression of a negative regulator block angiogenesis? | Inducible overexpression of Egr-1 or miR-1-3p in endothelial cells |
| Can a tagged protein be used to track localization during sprouting? | Tagged knock-in of EPLIN or JNK in endothelial cells |
| What is the effect of a microRNA on endothelial proliferation? | Overexpression or inhibition of miR-93-5p in HUVECs |
| Can CRISPR library screening identify novel negative regulators? | Genome-wide CRISPR knockout screen in endothelial cells under sprouting conditions |
How to Study the negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Global gene expression changes | Identify pathways altered during negative regulation |
| MicroRNA profiling | Levels of specific microRNAs | Biomarker discovery for AAA (e.g., miR-1-3p) |
| Spheroid sprouting assay | Endothelial sprout formation and proliferation | Test genetic manipulations in vitro |
| CRISPR knockout screen | Loss-of-function phenotypes | Discover novel negative regulators |
| Western blot | Protein expression and phosphorylation | Validate signaling changes (e.g., JNK) |
| Immunofluorescence | Protein localization and cell morphology | Study EPLIN or Egr-1 in endothelial cells |
| qRT-PCR | mRNA and microRNA levels | Confirm expression changes after CRISPR editing |
| Co-immunoprecipitation | Protein-protein interactions | Map regulatory complexes |
RNA Sequencing and MicroRNA Profiling
RNA sequencing can quantify changes in gene expression associated with negative regulation of endothelial proliferation. MicroRNA profiling, such as measuring miR-1-3p levels, has been used to identify biomarkers in abdominal aortic aneurysm. These methods help uncover regulatory networks involving microRNAs and their targets.
Endothelial Sprouting Assays
In vitro sprouting assays, such as the spheroid sprouting assay or aortic ring assay, allow direct observation of endothelial cell proliferation during sprouting. These assays can be combined with genetic manipulation to test the role of specific genes in GO:1903588.
CRISPR-Based Functional Screens
CRISPR knockout or activation screens in endothelial cells can identify genes that negatively regulate proliferation during sprouting. Such screens have the power to uncover novel regulators and validate candidates like EPLIN or JNK.
Protein Interaction and Signaling Studies
Co-immunoprecipitation, Western blotting, and phospho-proteomics can dissect signaling pathways involving JNK, Egr-1, and other regulators. These methods reveal how negative regulatory signals are transduced to the cell cycle machinery.
How CRISPR Can Be Used to Study GO:1903588 negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis
Knockout
CRISPR knockout of candidate genes such as MAPK8 (JNK) or EPLIN in endothelial cells can reveal their role in negative regulation of proliferation during sprouting. For example, knocking out EPLIN may enhance angiogenesis, consistent with its down-regulation by miR-93-5p. Knockout of JNK could reduce angiogenic potential, supporting its positive regulatory role.
Point Mutation
Introducing point mutations in genes like EPLIN or EGR1 can dissect specific functional domains. For instance, mutating phosphorylation sites in Egr-1 may affect its ability to block angiogenesis. Such models help distinguish between different regulatory mechanisms.
Knock-in
Knock-in of tagged versions of proteins (e.g., GFP-EPLIN) allows real-time tracking of localization and dynamics during sprouting. This approach can reveal how negative regulators are spatially controlled. Knock-in of mutant alleles can also model disease-associated variants.
Overexpression
Overexpression of negative regulators such as Egr-1 or miR-1-3p in endothelial cells can suppress proliferation and angiogenesis. Sustained Egr-1 expression blocks tumor growth, demonstrating the therapeutic potential of enhancing this process. Overexpression models are valuable for testing anti-angiogenic strategies.
How EDITGENE Supports negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis Research
Researchers studying negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis-related genes often need to determine whether a candidate gene is causally involved in this process or merely correlated with it. EDITGENE provides a comprehensive suite of CRISPR-based services to enable such causal investigations, from knockout to overexpression and library screening.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis research.
Frequently Asked Questions About negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis
What is GO:1903588?
GO:1903588 is a Gene Ontology biological process term that describes any process that stops, prevents, or reduces the frequency, rate, or extent of blood vessel endothelial cell proliferation specifically during sprouting angiogenesis.
What genes are involved in negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis?
Key genes include MIR1-3P, MIR93-5P, EPLIN, MAPK8 (JNK), and EGR1, among others, as reported in published studies.
How is this process studied experimentally?
Researchers use endothelial sprouting assays, RNA sequencing, microRNA profiling, and CRISPR-based screens to study this process.
Why is negative regulation of endothelial proliferation important in cancer?
Tumors rely on angiogenesis; restoring negative regulation can block tumor growth, as shown with sustained Egr-1 expression.
What is the role of miR-1-3p in this process?
miR-1-3p is a circulating biomarker for abdominal aortic aneurysm and may influence endothelial proliferation, though its exact role in GO:1903588 requires further study.
How does miR-93-5p affect sprouting angiogenesis?
miR-93-5p enhances growth and angiogenesis by down-regulating EPLIN, thereby potentially relieving negative regulation of endothelial proliferation.
What is the function of JNK in endothelial proliferation?
JNK acts as a positive regulator of angiogenic potential in endothelial cells, so its inhibition may contribute to negative regulation.
Can CRISPR be used to study this GO term?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models in endothelial cells are powerful tools to dissect the regulators of this process.
What diseases are associated with dysregulation of this process?
Dysregulation is linked to abdominal aortic aneurysm, tumor angiogenesis, and other vascular disorders.
What services does EDITGENE offer for studying this process?
EDITGENE provides CRISPR knockout, point mutation, knock-in, overexpression cell models, CRISPR library screening, and bioinformatics services to study genes involved in GO:1903588.
Conclusion
GO:1903588 represents a critical control point in vascular biology, ensuring that endothelial cell proliferation is appropriately restrained during sprouting angiogenesis. Dysregulation of this process contributes to diseases such as abdominal aortic aneurysm and cancer, making it a compelling target for therapeutic intervention. Advances in CRISPR-based models and high-throughput screening will continue to uncover the molecular players and regulatory networks that govern this process, offering new opportunities for drug discovery and precision medicine.
References
- 1. Jing J et al.. 2023. Clinical value of serum miR-1-3p as a potential circulating biomarker for abdominal aortic aneurysm.. Ann Med 55(2):2260395 PMID: 37751480
- 2. Liang L et al.. 2017. MiR-93-5p enhances growth and angiogenesis capacity of HUVECs by down-regulating EPLIN.. Oncotarget 8(63):107033-107043 PMID: 29291009
- 3. Uchida C et al.. 2008. JNK as a positive regulator of angiogenic potential in endothelial cells.. Cell Biol Int 32(7):769-76 PMID: 18455449
- 4. Lucerna M et al.. 2006. Sustained expression of early growth response protein-1 blocks angiogenesis and tumor growth.. Cancer Res 66(13):6708-13 PMID: 16818645
