GO:1903587 regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis: Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1903587 describes the biological process that modulates the frequency, rate, or extent of endothelial cell proliferation specifically during sprouting angiogenesis, a key step in new blood vessel formation [1, 7].
• This process is controlled by a balance of pro- and anti-angiogenic signals, including VEGF, FGF, BMP, and Notch pathways, which converge on endothelial cell cycle entry and migration [2, 4, 6].
• Endothelial progenitor cells and proteases contribute to the sprouting process by remodeling the extracellular matrix and releasing growth factors.
• Dysregulation of this process underlies numerous diseases, including cancer, retinopathies, and neurological disorders with blood-brain barrier breakdown [1, 7].
• Key genes such as VEGFA, KDR, FGFR1, and EFNB2 are central to the regulation of sprouting angiogenesis and are frequent targets in vascular research [2, 4, 5].
• CRISPR-based models (knockout, knock-in, overexpression) enable precise dissection of gene function in endothelial cell proliferation during sprouting [3, 5].
Description
Sprouting angiogenesis is the process by which new blood vessels emerge from pre-existing ones, a fundamental event in development, tissue repair, and disease. Central to this process is the proliferation of endothelial cells, which must be tightly regulated to ensure proper vessel formation. The Gene Ontology term GO:1903587, regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis, captures the biological processes that modulate the frequency, rate, or extent of endothelial cell proliferation specifically in the context of sprouting. This term is distinct from general endothelial proliferation because it encompasses the unique signaling and cellular behaviors that occur during sprouting, such as tip cell selection and stalk cell elongation [2, 6]. Understanding GO:1903587 is critical for researchers studying vascular development, tumor angiogenesis, and ischemic diseases. The process is orchestrated by a complex interplay of growth factors, receptors, and intracellular signaling cascades that ultimately control cell cycle progression [4, 5]. For example, VEGF signaling through VEGFR2 (KDR) is a primary driver of endothelial proliferation during sprouting, while Notch and BMP signaling modulate the response to ensure coordinated sprout extension [2, 6]. Disruption of these regulatory mechanisms leads to pathological angiogenesis, as seen in cancer, diabetic retinopathy, and age-related macular degeneration. This article provides a comprehensive overview of GO:1903587, integrating authoritative QuickGO annotations with real PubMed literature. We cover the molecular mechanisms, key genes, disease associations, and cutting-edge research methods, including CRISPR-based models, to support both basic and translational vascular biology.
regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis At A Glance
| GO ID | GO:1903587 |
|---|---|
| GO term | regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis |
| Ontology | biological_process |
| Synonym | regulation of blood vessel endothelial cell proliferation during sprouting angiogenesis |
| Definition | Any process that modulates the frequency, rate or extent of blood vessel endothelial cell proliferation involved in sprouting angiogenesis. |
| Major function | Controls endothelial cell division during new blood vessel sprouting. |
| Related processes | Sprouting angiogenesis, endothelial cell proliferation, VEGF signaling, Notch signaling. |
| Key regulators | VEGFA, KDR, FGFR1, EFNB2, BMP signaling components. |
| Disease relevance | Cancer, retinopathies, blood-brain barrier disorders. |
What Is GO:1903587?
GO:1903587, regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis, is defined as any process that modulates the frequency, rate, or extent of blood vessel endothelial cell proliferation specifically during sprouting angiogenesis. In other words, it encompasses all molecular and cellular events that control how often and how much endothelial cells divide when they are forming new sprouts from existing vessels. This regulation ensures that proliferation is spatially and temporally coordinated with other sprouting behaviors, such as migration and lumen formation.
Why Is regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis Important in Cell Biology?
GO:1903587 is important because it defines the regulatory layer that ensures endothelial cell proliferation is appropriately coupled to sprouting angiogenesis. This process is essential for embryonic development, wound healing, and tissue regeneration, but its dysregulation contributes to numerous pathologies, including tumor angiogenesis, diabetic retinopathy, and neurodegenerative conditions with vascular components [1, 7]. By studying this term, researchers can identify molecular targets that selectively modulate pathological angiogenesis without affecting normal vascular homeostasis.
• Controls endothelial cell proliferation during sprouting, a key step in new blood vessel formation.
• Integrates multiple signaling pathways, including VEGF, FGF, BMP, and Notch, to coordinate sprout growth [2, 4, 6].
• Dysregulation leads to excessive or insufficient angiogenesis in cancer, retinopathies, and ischemic diseases.
• Plays a role in blood-brain barrier maintenance and response to pericyte loss.
• Involves endothelial progenitor cells and proteases that remodel the extracellular matrix.
• Serves as a target for anti-angiogenic therapies in oncology and ophthalmology.
• Provides a framework for understanding vascular contributions to neurological disorders.
• Enables precise genetic dissection using CRISPR models to identify causal genes [3, 5].
What Happens During regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis?
Initiation by Pro-angiogenic Signals
In simple terms: The process starts when growth factors tell endothelial cells to divide and form new sprouts.
Sprouting angiogenesis is initiated by pro-angiogenic factors such as VEGF, which bind to receptors on endothelial cells and activate signaling cascades that promote proliferation [2, 7]. VEGF-A signaling through VEGFR2 (KDR) is a primary driver, leading to downstream activation of MAPK/ERK and PI3K/AKT pathways that stimulate cell cycle entry. FGF signaling also contributes to endothelial proliferation during sprouting, often in a complementary or synergistic manner with VEGF. The balance between these pro-angiogenic signals and anti-angiogenic cues determines whether endothelial cells enter the cell cycle and participate in sprout formation.
Tip and Stalk Cell Specification
In simple terms: Some endothelial cells become leaders (tip cells) and others become followers (stalk cells), and their proliferation is regulated differently.
During sprouting, endothelial cells adopt specialized phenotypes: tip cells guide the sprout and proliferate less, while stalk cells proliferate to elongate the sprout [2, 6]. Notch signaling, activated by Delta-like 4 (DLL4) in tip cells, suppresses proliferation in neighboring cells to maintain a balanced sprout. This lateral inhibition ensures that only appropriate numbers of endothelial cells proliferate, preventing excessive sprouting. The regulation of proliferation in tip versus stalk cells is a key aspect of GO:1903587.
Cell Cycle Progression and Metabolic Control
In simple terms: Endothelial cells need energy and building blocks to divide, and this is tightly controlled.
Endothelial cell proliferation during sprouting requires metabolic reprogramming to support rapid cell division. FGF signaling promotes glycolysis and other metabolic pathways to meet the biosynthetic demands of proliferating endothelial cells. Key metabolic regulators, such as mTOR and MYC, integrate growth factor signals with cell cycle machinery. Disruption of metabolic control impairs endothelial proliferation and sprouting, highlighting the interplay between metabolism and GO:1903587.
Modulation by BMP and Other Pathways
In simple terms: Other signals like BMP can either promote or inhibit endothelial proliferation depending on context.
BMP signaling has context-dependent effects on endothelial cell proliferation during sprouting. BMP9 and BMP10, acting through ALK1 and BMPR2, can promote or inhibit proliferation depending on the vascular bed and developmental stage. This versatility underscores the complexity of GO:1903587 regulation. Additionally, ephrin-B2 (EFNB2) signaling modulates VEGF-induced proliferation and sprouting, with loss of EFNB2 leading to defective angiogenesis. These pathways fine-tune the proliferative response to ensure proper vessel formation [2, 6].
Role of Endothelial Progenitor Cells and Proteases
In simple terms: Progenitor cells and enzymes that break down matrix help regulate proliferation during sprouting.
Endothelial progenitor cells (EPCs) can contribute to sprouting angiogenesis by providing a source of proliferating endothelial cells. Proteases, such as matrix metalloproteinases (MMPs), remodel the extracellular matrix to release bound growth factors and create space for sprouting, indirectly regulating endothelial proliferation. The interplay between EPCs, proteases, and resident endothelial cells is an important component of GO:1903587.
Key Genes Involved in GO:1903587 regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis
The following genes and proteins are central to the regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| VEGFA | Primary pro-angiogenic growth factor that stimulates endothelial proliferation | Target for anti-angiogenic therapy; knockout models show impaired sprouting [2, 7] |
| KDR (VEGFR2) | Receptor for VEGF-A; mediates proliferation signals | Key target for CRISPR knockout to study sprouting defects |
| FGFR1 | Receptor for FGF; promotes endothelial proliferation and metabolism | Knockout models reveal metabolic control of vascular development |
| EFNB2 | Ephrin-B2; regulates VEGF-induced angiogenesis and lymphangiogenesis | Knockout causes defective sprouting and proliferation |
| DLL4 | Notch ligand; suppresses excessive proliferation in stalk cells | Overexpression or knockout alters tip/stalk balance |
| NOTCH1 | Receptor for DLL4; modulates endothelial proliferation | Point mutations affect sprouting angiogenesis |
| BMPR2 | BMP receptor; context-dependent regulation of proliferation | Knockout models show vascular defects |
| ALK1 (ACVRL1) | BMP receptor; promotes or inhibits proliferation | Mutations linked to hereditary hemorrhagic telangiectasia |
| MMP2 | Protease that remodels ECM and releases growth factors | Knockout reduces sprouting in some models |
| MMP9 | Protease involved in ECM degradation during sprouting | Overexpression enhances angiogenesis |
| CD34 | Marker of endothelial progenitor cells | Used to isolate EPCs for proliferation studies |
| PECAM1 (CD31) | Endothelial cell adhesion molecule | Marker for endothelial cells in sprouting assays |
| CLDN5 | Tight junction protein in blood-brain barrier | Regulated during pericyte loss and angiogenesis |
| PLVAP | Endothelial marker involved in vascular permeability | Upregulated in angiogenic vessels |
| MYC | Transcription factor promoting cell cycle entry | Overexpression drives endothelial proliferation |
| MTOR | Kinase integrating growth signals with metabolism | Inhibition blocks endothelial proliferation |
| HIF1A | Hypoxia-inducible factor; induces VEGF and other pro-angiogenic genes | Knockout impairs sprouting |
| PDGFB | Recruits pericytes; indirectly regulates endothelial proliferation | Knockout leads to vessel instability |
How Is regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis Regulated?
The regulation of endothelial cell proliferation during sprouting angiogenesis is controlled by a network of signaling pathways. VEGF-A binding to VEGFR2 activates downstream cascades including PLCγ-ERK and PI3K-AKT, which promote cell cycle progression. FGF signaling supports proliferation by enhancing glycolytic metabolism. Notch signaling, via DLL4-NOTCH1, acts as a negative feedback to limit excessive proliferation in stalk cells. BMP signaling can either promote or inhibit proliferation depending on the receptor complex and context. Additionally, ephrin-B2 forward signaling modulates VEGFR2 internalization and downstream signaling, thereby influencing proliferation. Metabolic regulators such as mTOR and MYC integrate these signals with biosynthetic demands. This multilayered regulation ensures that endothelial proliferation is appropriately matched to sprout growth and tissue needs.
regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| VEGFA | Cancer, diabetic retinopathy | Xenograft models with VEGF overexpression; CRISPR knockout of VEGF in tumor cells |
| KDR | Cancer, angiogenesis disorders | Endothelial-specific KDR knockout mice; point mutations to block ligand binding |
| EFNB2 | Angiogenesis defects, lymphangiogenesis | Efnb2 knockout mice; knock-in of signaling-deficient mutants |
| BMPR2 | Hereditary hemorrhagic telangiectasia, pulmonary hypertension | BMPR2 knockout endothelial cells; point mutations |
| HIF1A | Ischemic diseases, cancer | HIF1A knockout mice; overexpression in endothelial cells |
Cancer and Tumor Angiogenesis
Tumors require new blood vessels to grow and metastasize, and they often hijack the regulation of endothelial cell proliferation during sprouting to promote angiogenesis. Overexpression of VEGF and other pro-angiogenic factors in the tumor microenvironment drives excessive endothelial proliferation, leading to abnormal, leaky vessels. Anti-angiogenic therapies targeting VEGF or its receptors aim to inhibit this process, but resistance often develops. Understanding GO:1903587 can inform the development of more effective anti-angiogenic strategies.
Retinopathies and Ocular Neovascularization
Pathological angiogenesis in the retina, as seen in diabetic retinopathy and age-related macular degeneration, involves dysregulated endothelial proliferation during sprouting. Hypoxia in the retina induces VEGF, which stimulates endothelial cells to proliferate and form new, fragile vessels that can leak and cause vision loss. Targeting the regulatory mechanisms of GO:1903587 is a major therapeutic approach in ophthalmology.
Blood-Brain Barrier and Neurological Disorders
The blood-brain barrier (BBB) is maintained by endothelial cells and pericytes, and its breakdown is associated with neurological disorders. Pericyte loss leads to increased endothelial proliferation and angiogenesis, contributing to BBB dysfunction. Single-cell studies have revealed that pericyte loss alters the transcriptome of endothelial cells, affecting proliferation and sprouting. Thus, GO:1903587 is relevant to understanding vascular contributions to neurodegeneration.
From regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X regulate endothelial proliferation during sprouting? | Endothelial-specific knockout (e.g., Cdh5-Cre; X fl/fl) |
| Does a specific point mutation in gene X affect its function in angiogenesis? | Knock-in of point mutant (e.g., Kdr kinase-dead) |
| Does overexpression of gene X enhance sprouting? | Endothelial-specific overexpression (e.g., Tie2-driven) |
| What is the role of gene X in tip vs stalk cells? | Mosaic knockout or overexpression using inducible systems |
| Can a tagged version of gene X reveal its localization? | Knock-in of fluorescent or epitope tag (e.g., GFP) |
| Is gene X required for developmental angiogenesis? | Germline knockout or conditional knockout in mice [2, 4] |
How to Study the regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis Process
| Method | What It Measures | Typical Application |
|---|---|---|
| In vitro sprouting assay | Sprout length, number, and proliferation | Testing pro- or anti-angiogenic factors |
| Single-cell RNA-seq | Transcriptomic profiles of endothelial cells | Identifying proliferating subpopulations |
| Intravital imaging | Real-time sprout dynamics and proliferation | Studying developmental or pathological angiogenesis [2, 7] |
| Phosphoproteomics | Kinase activity and signaling changes | Mapping VEGF/FGF pathways |
| EdU/BrdU incorporation | DNA synthesis as a measure of proliferation | Quantifying endothelial proliferation in vitro and in vivo |
| CRISPR knockout screening | Gene function on a large scale | Identifying novel regulators of sprouting |
| Western blot | Protein expression and phosphorylation | Validating signaling changes |
| Immunofluorescence | Localization of proteins in sprouting vessels | Visualizing tip/stalk cell markers |
In Vitro Sprouting Assays
Endothelial cell sprouting can be studied in vitro using three-dimensional co-culture systems, such as HUVECs co-cultured with fibroblasts or dental pulp stem cells (DPSCs). These assays allow quantification of sprout length, number, and endothelial proliferation. Treatment with TGF-β1 or VEGF can modulate sprouting, and gene knockdown or knockout can be used to assess the role of specific regulators.
Single-Cell RNA Sequencing
Single-cell RNA sequencing (scRNA-seq) enables transcriptomic profiling of endothelial cells during sprouting angiogenesis. This method can identify subpopulations of proliferating endothelial cells and reveal gene expression changes in response to pericyte loss or other perturbations. It is particularly useful for understanding heterogeneity within the sprouting vasculature.
Genetic Lineage Tracing and Imaging
Lineage tracing using inducible Cre-lox systems allows researchers to follow the fate of proliferating endothelial cells during sprouting. Intravital imaging of zebrafish or mouse retinas can visualize sprout formation and endothelial proliferation in real time [2, 7]. These techniques provide spatial and temporal resolution of GO:1903587 regulation.
Proteomics and Phosphoproteomics
Mass spectrometry-based proteomics can quantify changes in protein expression and phosphorylation during endothelial proliferation. This approach can identify signaling nodes downstream of VEGF or FGF that regulate cell cycle entry. Phosphoproteomics is particularly useful for mapping kinase pathways involved in GO:1903587.
How CRISPR Can Be Used to Study GO:1903587 regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis
Knockout
CRISPR-Cas9 knockout of candidate genes in endothelial cells or mouse models is a powerful approach to determine their role in GO:1903587. For example, knockout of Kdr (VEGFR2) abolishes VEGF-induced proliferation and sprouting. Endothelial-specific knockout using Cdh5-Cre or Tie2-Cre allows study of gene function in vivo without developmental lethality. Pooled CRISPR screens can identify novel regulators of endothelial proliferation during sprouting.
Point Mutation
Knock-in of point mutations using CRISPR can dissect specific signaling domains or phosphorylation sites. For instance, mutation of VEGFR2 tyrosine residues can reveal their contribution to proliferation versus migration. Point mutations in EFNB2 or BMPR2 can model human disease variants and assess their impact on sprouting angiogenesis [2, 6]. This approach provides mechanistic insights beyond simple knockout.
Knock-in
CRISPR-mediated knock-in of reporter genes (e.g., GFP, luciferase) or epitope tags allows visualization and tracking of endothelial cells during sprouting. Knock-in of Cre recombinase under an endothelial-specific promoter enables lineage tracing. Additionally, knock-in of human disease mutations into mouse genes can create accurate models for studying GO:1903587 in pathology.
Overexpression
CRISPR activation (CRISPRa) or transgenic overexpression can drive candidate genes to supraphysiological levels to test sufficiency in promoting endothelial proliferation and sprouting. For example, overexpression of VEGF-A or FGF2 enhances sprouting in vitro and in vivo [3, 4]. Inducible overexpression systems allow temporal control, which is critical for studying dynamic processes like angiogenesis.
How EDITGENE Supports regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis Research
Researchers studying 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 endothelial proliferation, and to dissect the precise molecular mechanisms. EDITGENE provides a comprehensive suite of CRISPR-based services to accelerate this research, from gene knockout to precise point mutations and overexpression models.
Contact EDITGENE today to design your custom CRISPR model for regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis research.
Frequently Asked Questions About regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis
What is GO:1903587?
GO:1903587 is a Gene Ontology term for the biological process that regulates the frequency, rate, or extent of blood vessel endothelial cell proliferation specifically during sprouting angiogenesis.
What genes are involved in regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis?
Key genes include VEGFA, KDR (VEGFR2), FGFR1, EFNB2, DLL4, NOTCH1, BMPR2, and ALK1, among others [2, 4, 5, 6].
How is endothelial cell proliferation regulated during sprouting?
It is regulated by a balance of pro-angiogenic signals (VEGF, FGF) and modulatory signals (Notch, BMP, ephrin-B2) that control cell cycle entry and metabolism [2, 4, 6].
What diseases are associated with dysregulation of sprouting angiogenesis?
Cancer, diabetic retinopathy, age-related macular degeneration, and blood-brain barrier disorders are associated with dysregulated sprouting angiogenesis [1, 7].
What methods are used to study GO:1903587?
Common methods include in vitro sprouting assays, single-cell RNA-seq, intravital imaging, phosphoproteomics, and CRISPR screens [1, 3, 4, 5].
How can CRISPR be used to study this process?
CRISPR knockout, point mutation knock-in, reporter knock-in, and overexpression models allow precise dissection of gene function in endothelial proliferation during sprouting [2, 3, 5].
What is the role of VEGF in sprouting angiogenesis?
VEGF-A binding to VEGFR2 (KDR) activates signaling cascades that promote endothelial cell proliferation and sprout formation [2, 5].
What is the role of Notch signaling in sprouting?
Notch signaling, via DLL4-NOTCH1, suppresses excessive proliferation in stalk cells to maintain proper sprout architecture.
How do pericytes affect endothelial proliferation?
Pericyte loss leads to increased endothelial proliferation and angiogenesis, contributing to blood-brain barrier dysfunction.
What are endothelial progenitor cells and how do they relate to sprouting?
Endothelial progenitor cells (EPCs) are circulating cells that can contribute to sprouting angiogenesis by providing a source of proliferating endothelial cells and releasing proteases.
Conclusion
GO:1903587, regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis, is a critical biological process that integrates multiple signaling pathways to control endothelial cell division during new blood vessel formation. Its dysregulation is implicated in cancer, retinopathies, and neurological disorders, making it a prime target for therapeutic intervention. Advances in CRISPR-based models and single-cell technologies are providing unprecedented insights into the molecular mechanisms governing this process. EDITGENE offers a comprehensive suite of services to support researchers in dissecting the genetic and molecular basis of GO:1903587, from knockout and knock-in models to library screening and bioinformatics.
References
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- 2. Wang Y et al.. 2010. Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis.. Nature 465(7297):483-6 PMID: 20445537
- 3. Zhang Y et al.. 2021. DPSCs treated by TGF-β1 regulate angiogenic sprouting of three-dimensionally co-cultured HUVECs and DPSCs through VEGF-Ang-Tie2 signaling.. Stem Cell Res Ther 12(1):281 PMID: 33971955
- 4. Yu P et al.. 2017. FGF-dependent metabolic control of vascular development.. Nature 545(7653):224-228 PMID: 28467822
- 5. Zink J et al.. 2021. EVL regulates VEGF receptor-2 internalization and signaling in developmental angiogenesis.. EMBO Rep 22(2):e48961 PMID: 33512764
- 6. Kulikauskas MR et al.. 2022. The versatility and paradox of BMP signaling in endothelial cell behaviors and blood vessel function.. Cell Mol Life Sci 79(2):77 PMID: 35044529
- 7. Joo JH et al.. 2026. Retinal angiogenesis: Development and pathophysiology.. Handb Clin Neurol 217:179-201 PMID: 42106176
- 8. Laurenzana A et al.. 2015. Endothelial Progenitor Cells in Sprouting Angiogenesis: Proteases Pave the Way.. Curr Mol Med 15(7):606-20 PMID: 26321757
