GO:1905564 positive regulation of vascular endothelial cell proliferation: Signaling Mechanisms, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1905564 describes any process that activates or increases the frequency, rate or extent of vascular endothelial cell proliferation, a central event in angiogenesis and vascular repair [1, 3].
• Key molecular drivers include VEGFA-NF-kB signaling, lactate-induced M2-like macrophage polarization, and EPAS1-mediated endothelial fatty acid uptake [1, 4, 8].
• Non-coding RNAs such as LINC00460 and microRNAs like miR-24-3p modulate endothelial proliferation by post-transcriptional mechanisms.
• Endothelial proliferation is tightly coupled to metabolic cues, including glycolysis in pericytes and lactate exchange between cell types [1, 2].
• Dysregulated positive regulation of vascular endothelial cell proliferation contributes to tumor angiogenesis, atherosclerosis, and impaired muscle regeneration [1, 4, 8].
• CRISPR knockout, knock-in, and overexpression models are essential to dissect causal roles of candidate genes in endothelial proliferation [3, 6].
Description
GO:1905564, positive regulation of vascular endothelial cell proliferation, is a biological process term that captures any molecular event that activates or increases the frequency, rate, or extent of vascular endothelial cell proliferation [1, 3]. This process is fundamental to angiogenesis, the formation of new blood vessels from pre-existing ones, and is required for tissue growth, wound healing, and recovery from ischemia [1, 7]. Because endothelial cells line the inner surface of all blood vessels, their controlled proliferation ensures adequate oxygen and nutrient delivery while preventing pathological vascular overgrowth [4, 8]. Researchers study this term to understand how signals from growth factors, metabolites, and mechanical forces converge on endothelial cell cycle entry [1, 2, 8]. The QuickGO definition emphasizes positive regulation, distinguishing it from negative regulation or baseline proliferation, and highlights the need to identify specific activators and pathways [3, 6]. In cancer, excessive endothelial proliferation supports tumor angiogenesis, making this process a therapeutic target. In cardiovascular disease, impaired endothelial proliferation contributes to atherosclerosis and defective repair after injury [5, 8]. Thus, GO:1905564 provides a framework for integrating molecular, cellular, and physiological data on vascular growth control [1, 3, 7].
positive regulation of vascular endothelial cell proliferation At A Glance
| GO ID | GO:1905564 |
|---|---|
| GO term | positive regulation of vascular endothelial cell proliferation |
| Ontology | biological_process |
| Synonym | activation of vascular endothelial cell proliferation; up regulation of vascular endothelial cell proliferation; up-regulation of vascular endothelial cell proliferation; upregulation of vascular endothelial cell proliferation |
| Definition | Any process that activates or increases the frequency, rate or extent of vascular endothelial cell proliferation. |
| Major function | Stimulation of endothelial cell division during angiogenesis, vascular repair, and tissue regeneration. |
| Related processes | Angiogenesis, endothelial cell migration, tube formation, vascular permeability. |
| Key regulators | VEGFA, NF-kB, EPAS1, lactate, LINC00460, miR-24-3p, ZO-1, YB-1. |
What Is GO:1905564?
In our own words, GO:1905564 refers to any biological process that stimulates or enhances the proliferation of vascular endothelial cells, which are the cells that form the inner lining of blood vessels. This includes signals that promote cell cycle progression, increase mitotic rate, or expand endothelial cell numbers. The term is a positive regulation term, meaning it specifically covers activators or up-regulators of endothelial proliferation, as opposed to inhibitors or baseline maintenance. It is used in gene ontology annotations to describe the roles of genes and pathways that drive angiogenesis and vascular remodeling.
Why Is positive regulation of vascular endothelial cell proliferation Important in Cell Biology?
Understanding positive regulation of vascular endothelial cell proliferation is critical because this process underlies both normal vascular development and numerous diseases. It is essential for recovery from ischemic injury, where endothelial proliferation restores blood flow to damaged muscle. In cancer, tumor cells often hijack this process to promote angiogenesis, supplying nutrients and oxygen to growing tumors. In atherosclerosis, disturbed flow and metabolic signals can alter endothelial proliferation and contribute to plaque formation. Moreover, endothelial proliferation is tightly linked to pericyte function and metabolic crosstalk, as shown by hexokinase 2-driven glycolysis in pericytes that affects tumor blood vessel abnormalities. Therefore, identifying the genes and pathways that positively regulate endothelial proliferation offers opportunities for therapeutic intervention in cardiovascular disease, cancer, and regenerative medicine [3, 5, 6].
• Drives angiogenesis, which is required for tissue growth, wound healing, and recovery from ischemia [1, 7].
• Supports tumor angiogenesis; inhibitors of endothelial proliferation are investigated as anti-cancer strategies.
• Contributes to vascular repair after injury and in ischemic muscle regeneration through lactate-mediated macrophage polarization.
• Is modulated by metabolic signals such as glycolysis in pericytes, linking vascular proliferation to metabolic state.
• Involves non-coding RNAs like LINC00460 that sponge miR-24-3p to enhance endothelial proliferation.
• Is influenced by endothelial fatty acid uptake via EPAS1, which attenuates atherosclerosis initiation at disturbed flow sites.
• Requires tight regulation; excessive proliferation can lead to vascular abnormalities and tumor progression [2, 4].
• Serves as a readout for testing pro- or anti-angiogenic compounds in preclinical models [3, 5].
• Involves stress granule formation and RNA-binding proteins like YB-1 and ZO-1 during angiogenesis.
• Provides a mechanistic link between inflammation, NF-kB signaling, and VEGFA expression in colorectal cancer.
What Happens During positive regulation of vascular endothelial cell proliferation?
Initiation by Growth Factors and Metabolic Cues
In simple terms: The process starts when signals like growth factors or metabolites tell endothelial cells to divide.
Positive regulation of vascular endothelial cell proliferation is initiated by extracellular stimuli such as vascular endothelial growth factor A (VEGFA), which activates NF-kB signaling to promote endothelial cell cycle entry. Lactate produced by endothelial cells can also act as a signal that induces M2-like macrophage polarization, which in turn supports muscle regeneration and angiogenesis. In pericytes, hexokinase 2-driven glycolysis enhances contractility and contributes to tumor blood vessel abnormalities, indirectly affecting endothelial proliferation. These diverse cues converge on endothelial cells to trigger proliferative programs [1, 4].
Intracellular Signaling and Gene Expression Changes
In simple terms: Inside the cell, specific pathways switch on genes that drive cell division.
Upon stimulation, signaling cascades such as the NF-kB pathway induce the expression of VEGFA and other pro-angiogenic factors. The transcription factor EPAS1 (HIF-2alpha) attenuates atherosclerosis initiation by regulating endothelial fatty acid uptake, which can influence endothelial proliferation under disturbed flow. Non-coding RNAs also play a role: LINC00460 stimulates vascular endothelial cell proliferation by downregulating miRNA-24-3p, thereby relieving repression of proliferative genes. Additionally, ZO-1 interacts with YB-1 to regulate stress granule formation during angiogenesis, impacting endothelial cell behavior.
Cell Cycle Progression and Mitosis
In simple terms: The endothelial cell moves through the cell cycle and divides into two cells.
The ultimate outcome of positive regulation is increased frequency or rate of endothelial cell proliferation, which requires progression through the cell cycle and mitosis. This step is driven by the cumulative effects of growth factor signaling, metabolic support, and gene expression changes [1, 4]. For example, lactate-mediated macrophage polarization creates a pro-regenerative environment that supports endothelial proliferation during muscle regeneration. In tumors, NF-kB-induced VEGFA promotes endothelial proliferation to sustain angiogenesis. The process is tightly regulated to avoid excessive or insufficient vascular growth [2, 8].
Integration with Vascular Remodeling
In simple terms: Newly divided endothelial cells help build and remodel blood vessels.
After proliferation, endothelial cells participate in tube formation and vessel stabilization, often in coordination with pericytes and other mural cells. Thrombospondin 1 and Reelin act through Vldlr to regulate cardiac growth and repair, implicating endothelial proliferation in cardiac remodeling. Pentraxin-3 is associated with endothelial dysfunction, highlighting the balance between proliferative and dysfunctional states. Thus, positive regulation of endothelial proliferation is integrated with broader vascular remodeling processes [2, 5, 7].
Key Genes Involved in GO:1905564 positive regulation of vascular endothelial cell proliferation
The following genes and proteins have been experimentally linked to positive regulation of vascular endothelial cell proliferation, based on the verified literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| VEGFA | Induces endothelial proliferation via NF-kB pathway | Target in tumor angiogenesis and colorectal cancer |
| NF-kB | Transcription factor activating VEGFA expression | Mediates inflammatory and angiogenic signaling |
| EPAS1 (HIF-2alpha) | Regulates endothelial fatty acid uptake | Attenuates atherosclerosis at disturbed flow sites |
| HK2 | Hexokinase 2 drives glycolysis in pericytes | Links metabolism to tumor blood vessel abnormalities |
| LINC00460 | Long non-coding RNA that downregulates miR-24-3p | Stimulates endothelial proliferation |
| miR-24-3p | MicroRNA repressed by LINC00460 | Modulates endothelial proliferation |
| ZO-1 | Tight junction protein interacting with YB-1 | Regulates stress granule formation during angiogenesis |
| YB-1 | RNA-binding protein involved in stress granules | Modulates endothelial cell behavior during angiogenesis |
| PTX3 | Pentraxin-3, marker of endothelial dysfunction | Associated with impaired endothelial function |
| THBS1 | Thrombospondin 1, matricellular protein | Regulates cardiac growth and repair via Vldlr |
| VLDLR | Reelin receptor | Mediates effects on cardiac growth and repair |
| Lactate | Metabolite inducing M2-like macrophage polarization | Supports muscle regeneration from ischemia |
| B7-H3 | Immune checkpoint molecule promoting angiogenesis | Activates NF-kB to induce VEGFA in colorectal cancer |
How Is positive regulation of vascular endothelial cell proliferation Regulated?
Positive regulation of vascular endothelial cell proliferation is controlled at multiple levels. Growth factor signaling through VEGFA and NF-kB provides a major transcriptional axis. Metabolic regulation occurs via lactate production and hexokinase 2-driven glycolysis in pericytes, which can influence endothelial behavior [1, 2]. Non-coding RNAs such as LINC00460 and miR-24-3p add post-transcriptional control. EPAS1 modulates endothelial fatty acid uptake, affecting proliferation under flow conditions. Additionally, stress granule formation regulated by ZO-1 and YB-1 may impact angiogenic responses. These layers ensure that endothelial proliferation is matched to physiological needs and can be dysregulated in disease [5, 7].
positive regulation of vascular endothelial cell proliferation and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| VEGFA / NF-kB | Colorectal cancer angiogenesis | Xenograft mouse models with endothelial-specific NF-kB knockout |
| EPAS1 | Atherosclerosis initiation | Disturbed flow models in EPAS1 knockout mice |
| HK2 | Tumor blood vessel abnormalities | Pericyte-specific HK2 knockout mice |
| LINC00460 / miR-24-3p | Endothelial proliferation in cancer | Endothelial cell lines with LINC00460 overexpression or knockdown |
| ZO-1 / YB-1 | Angiogenesis and stress granule formation | Endothelial-specific ZO-1 knockout zebrafish or mice |
Cancer and Tumor Angiogenesis
In colorectal cancer, B7-H3 promotes angiogenesis by activating the NF-kB pathway to induce VEGFA expression, which in turn stimulates vascular endothelial cell proliferation. This highlights how tumor cells exploit positive regulation of endothelial proliferation to support their growth. Targeting this process is a major strategy in anti-angiogenic therapy.
Atherosclerosis and Cardiovascular Disease
EPAS1 attenuates atherosclerosis initiation at disturbed flow sites by regulating endothelial fatty acid uptake, linking metabolic control of endothelial proliferation to cardiovascular disease. Pentraxin-3 is a marker of endothelial dysfunction, and its levels correlate with impaired vascular health. Thrombospondin 1 and Reelin act through Vldlr to regulate cardiac growth and repair, implicating endothelial proliferation in cardiac remodeling.
Ischemic Muscle Regeneration
Endothelial lactate controls muscle regeneration from ischemia by inducing M2-like macrophage polarization, which supports endothelial proliferation and angiogenesis. This demonstrates the importance of metabolic crosstalk between endothelial cells and immune cells in tissue repair.
Tumor Blood Vessel Abnormalities
Hexokinase 2-driven glycolysis in pericytes activates their contractility, leading to tumor blood vessel abnormalities. This metabolic reprogramming in pericytes can affect endothelial proliferation and vessel function, contributing to the chaotic tumor vasculature.
From positive regulation of vascular endothelial cell proliferation-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X promote endothelial proliferation? | CRISPR knockout of gene X in human umbilical vein endothelial cells (HUVECs) followed by proliferation assays |
| Does a point mutation in gene Y alter its pro-proliferative function? | CRISPR point mutation knock-in in endothelial cells |
| Does overexpression of gene Z increase angiogenesis in vivo? | Endothelial-specific overexpression via knock-in of a constitutive promoter |
| Does a tagged version of protein W localize to stress granules? | CRISPR knock-in of a fluorescent tag (e.g., GFP) at the endogenous locus |
| Is the metabolic regulation of endothelial proliferation dependent on HK2? | Pericyte-specific HK2 knockout mice |
| Does lactate signaling from endothelial cells affect macrophage polarization? | Endothelial-specific lactate transporter knockout mice |
How to Study the positive regulation of vascular endothelial cell proliferation Process
| Method | What It Measures | Typical Application |
|---|---|---|
| EdU incorporation | DNA synthesis and cell proliferation | Quantify endothelial proliferation in vitro |
| RNA-seq | Global gene expression changes | Identify pathways regulating endothelial proliferation |
| Small RNA-seq | MicroRNA expression | Discover miRNAs like miR-24-3p involved in proliferation |
| Seahorse assay | Glycolytic and oxidative metabolism | Assess metabolic control of endothelial proliferation |
| Confocal microscopy | Vessel morphology and protein localization | Visualize angiogenesis and stress granules |
| Western blot | Protein expression and phosphorylation | Detect NF-kB activation and VEGFA levels |
| Lactate assay | Lactate production | Measure metabolic crosstalk in muscle regeneration |
Proliferation Assays
Standard methods to measure positive regulation of vascular endothelial cell proliferation include EdU incorporation, Ki-67 staining, and cell counting assays. These are used to quantify the frequency or rate of endothelial cell division after genetic or pharmacological manipulation.
Transcriptomic and Non-coding RNA Analysis
RNA-seq and small RNA-seq can identify changes in gene expression and microRNAs such as miR-24-3p that regulate endothelial proliferation. LINC00460 was discovered to stimulate proliferation by downregulating miR-24-3p using such approaches.
Metabolic Flux Analysis
Seahorse extracellular flux analysis and lactate measurements can assess glycolytic activity in pericytes and endothelial cells, linking metabolism to proliferation [1, 2]. Hexokinase 2-driven glycolysis in pericytes was studied using these methods.
Imaging of Angiogenesis
In vivo imaging techniques such as confocal microscopy of zebrafish or mouse retinal vasculature allow visualization of endothelial proliferation and vessel formation [3, 7]. Stress granule formation can be imaged using fluorescently tagged YB-1.
How CRISPR Can Be Used to Study GO:1905564 positive regulation of vascular endothelial cell proliferation
Knockout
CRISPR knockout of candidate genes such as LINC00460 or ZO-1 in endothelial cells can determine whether they are required for positive regulation of vascular endothelial cell proliferation [3, 6]. Knockout models help establish causality and identify essential regulators.
Point Mutation
Introducing specific point mutations in genes like EPAS1 can reveal how single amino acid changes affect endothelial proliferation and atherosclerosis initiation. This approach is useful for studying disease-associated variants.
Knock-in
Knock-in of fluorescent tags or reporter genes at endogenous loci, such as tagging YB-1, allows real-time visualization of protein localization during angiogenesis. Knock-in of constitutive promoters can drive overexpression of pro-proliferative genes.
Overexpression
CRISPR activation (CRISPRa) or knock-in of strong promoters can overexpress genes like VEGFA to study their sufficiency in promoting endothelial proliferation. Overexpression models are valuable for testing therapeutic potential.
How EDITGENE Supports positive regulation of vascular endothelial cell proliferation Research
Researchers studying positive regulation of vascular endothelial cell proliferation-related genes often need to determine whether a candidate gene is causally involved in endothelial cell division or simply correlated with it. This requires precise genetic manipulation, which is where EDITGENE's CRISPR services can accelerate discovery.
Contact EDITGENE today to design your custom CRISPR model for positive regulation of vascular endothelial cell proliferation research.
Frequently Asked Questions About positive regulation of vascular endothelial cell proliferation
What is GO:1905564?
GO:1905564 is the Gene Ontology term for positive regulation of vascular endothelial cell proliferation, describing any process that activates or increases the frequency, rate, or extent of endothelial cell division [1, 3].
What genes are involved in positive regulation of vascular endothelial cell proliferation?
Key genes include VEGFA, NF-kB, EPAS1, HK2, LINC00460, miR-24-3p, ZO-1, YB-1, and PTX3, among others [1, 2, 3, 4, 5, 6, 8].
How is vascular endothelial cell proliferation regulated?
It is regulated by growth factors like VEGFA, metabolic cues such as lactate and glycolysis, non-coding RNAs, and transcription factors like NF-kB and EPAS1 [1, 2, 4, 6, 8].
Why is endothelial proliferation important in cancer?
Tumor cells can induce endothelial proliferation to promote angiogenesis, supplying nutrients and oxygen to the tumor, as seen in colorectal cancer via B7-H3 and NF-kB.
What diseases involve dysregulated endothelial proliferation?
Cancer, atherosclerosis, ischemic muscle injury, and tumor blood vessel abnormalities all involve dysregulated endothelial proliferation [1, 2, 4, 8].
How can CRISPR be used to study endothelial proliferation?
CRISPR knockout, point mutation, knock-in, and overexpression models allow researchers to test the causal role of specific genes in endothelial proliferation [3, 6, 8].
What methods measure endothelial cell proliferation?
EdU incorporation, Ki-67 staining, cell counting, and RNA-seq are common methods to measure endothelial proliferation.
What is the role of lactate in endothelial proliferation?
Endothelial lactate controls muscle regeneration from ischemia by inducing M2-like macrophage polarization, which supports endothelial proliferation.
How does EPAS1 affect endothelial proliferation?
EPAS1 attenuates atherosclerosis initiation at disturbed flow sites by regulating endothelial fatty acid uptake, which can influence proliferation.
What is the link between pericytes and endothelial proliferation?
Hexokinase 2-driven glycolysis in pericytes activates contractility and leads to tumor blood vessel abnormalities, indirectly affecting endothelial proliferation.
Conclusion
GO:1905564, positive regulation of vascular endothelial cell proliferation, is a vital biological process that integrates growth factor signaling, metabolic cues, and non-coding RNA networks to control blood vessel formation and repair [1, 3, 6]. Its dysregulation is implicated in cancer, atherosclerosis, and ischemic injury, making it a key area for therapeutic targeting [4, 5, 8]. Advances in CRISPR-based models and multi-omics methods continue to uncover new regulators and mechanisms [2, 7]. By leveraging these tools, researchers can translate findings into novel strategies for vascular disease and regenerative medicine.
References
- 1. Zhang J et al.. 2020. Endothelial Lactate Controls Muscle Regeneration from Ischemia by Inducing M2-like Macrophage Polarization.. Cell Metab 31(6):1136-1153.e7 PMID: 32492393
- 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. El Bakkouri Y et al.. 2024. ZO-1 interacts with YB-1 in endothelial cells to regulate stress granule formation during angiogenesis.. Nat Commun 15(1):4405 PMID: 38782923
- 4. Wang R et al.. 2020. B7-H3 promotes colorectal cancer angiogenesis through activating the NF-κB pathway to induce VEGFA expression.. Cell Death Dis 11(1):55 PMID: 31974361
- 5. Zlibut A et al.. 2019. Pentraxin-3 and endothelial dysfunction.. Adv Clin Chem 91:163-179 PMID: 31331488
- 6. Jia R et al.. 2022. LINC00460 Stimulates the Proliferation of Vascular Endothelial Cells by Downregulating miRNA-24-3p.. Dis Markers 2022:2524156 PMID: 35222741
- 7. Pei L et al.. 2024. Thrombospondin 1 and Reelin act through Vldlr to regulate cardiac growth and repair.. Basic Res Cardiol 119(1):169-192 PMID: 38147128
- 8. Pirri D et al.. 2024. EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid Uptake.. Circ Res 135(8):822-837 PMID: 39234692
