GO:2001213 negative regulation of vasculogenesis: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:2001213 (negative regulation of vasculogenesis) describes any process that stops, prevents, or reduces the frequency, rate, or extent of vasculogenesis, the de novo formation of blood vessels from angioblasts.
• Key negative regulators include soluble guidance cues such as semaphorins, which can inhibit endothelial cell migration and tube formation during vascular morphogenesis.
• VEGF and Notch signaling pathways are central to endothelial differentiation and arterial specification, and their modulation can suppress excessive vasculogenesis.
• The Med23 subunit of the Mediator complex supports angiogenesis and vascular integrity by negatively regulating angiopoietin-2 expression, illustrating transcriptional control of vessel formation.
• PKCε acts as a negative regulator of perivascular adipose tissue (PVAT)-derived vessel formation, linking metabolic tissue signaling to vasculogenesis inhibition.
• Dysregulation of negative regulation of vasculogenesis contributes to pathologies such as progeria-associated vascular dysfunction, where angiopoietin-2 can reverse endothelial cell defects.
Description
Vasculogenesis is the process by which endothelial precursor cells (angioblasts) differentiate and assemble into primitive blood vessels, establishing the initial vascular network during embryonic development and in some adult pathological settings. The Gene Ontology term GO:2001213, negative regulation of vasculogenesis, encompasses any process that stops, prevents, or reduces the frequency, rate, or extent of this vessel-forming program. Understanding how vasculogenesis is restrained is critical because excessive or misdirected vessel formation underlies disorders ranging from retinopathies to tumor progression, while insufficient restraint can lead to vascular malformations. Mechanistically, negative regulation of vasculogenesis is achieved through a balance of pro- and anti-angiogenic signals. Soluble factors such as semaphorins can directly inhibit endothelial cell migration and tube formation, acting as guidance cues that restrict vascular morphogenesis. The VEGF and Notch signaling axes are also pivotal: VEGF receptor signal transduction drives endothelial differentiation and arterial specification, and its negative modulation can suppress vasculogenic programs. Additionally, transcriptional cofactors such as Med23 maintain vascular integrity by repressing angiopoietin-2, a context-dependent regulator of endothelial quiescence. For researchers, GO:2001213 provides a framework to interrogate how tissues limit vascular expansion. This article synthesizes published findings on the molecular players, regulatory mechanisms, and experimental models used to study negative regulation of vasculogenesis, with an emphasis on CRISPR-based approaches for functional validation.
negative regulation of vasculogenesis At A Glance
| GO ID | GO:2001213 |
|---|---|
| GO term | negative regulation of vasculogenesis |
| Ontology | biological_process |
| Synonym | negative regulation of vascular morphogenesis |
| Major function | Stops, prevents, or reduces the frequency, rate, or extent of vasculogenesis |
| Related processes | Angiogenesis, endothelial cell differentiation, vascular morphogenesis |
| Key signaling pathways | VEGF, Notch, semaphorin, angiopoietin |
| Representative regulators | Semaphorins, PKCε, Med23, angiopoietin-2 |
| Disease relevance | Progeria, vascular malformations, cancer, retinopathies |
What Is GO:2001213?
According to the Gene Ontology, GO:2001213 (negative regulation of vasculogenesis) is defined as any process that stops, prevents, or reduces the frequency, rate, or extent of vasculogenesis. Vasculogenesis itself is the de novo formation of blood vessels from endothelial precursor cells, and its negative regulation can occur at multiple levels, including inhibition of endothelial differentiation, migration, proliferation, or tube assembly. This term is a biological process and is synonymous with negative regulation of vascular morphogenesis.
Why Is negative regulation of vasculogenesis Important in Cell Biology?
Negative regulation of vasculogenesis is essential for normal development and tissue homeostasis, preventing excessive or ectopic vessel formation that could disrupt organ function. Its dysregulation is implicated in a range of human diseases, including progeria-associated vascular dysfunction, where angiopoietin-2 can reverse endothelial cell defects, and in conditions characterized by abnormal vascular morphogenesis. Understanding the negative regulators of vasculogenesis offers therapeutic opportunities to modulate vessel growth in ischemic diseases, cancer, and developmental disorders.
• Prevents excessive vascular expansion during embryonic development.
• Maintains endothelial cell quiescence and vascular integrity.
• Modulates VEGF and Notch signaling to control arterial specification.
• Involved in progeria-associated vascular dysfunction, where angiopoietin-2 can reverse endothelial defects.
• Semaphorins act as negative regulators of vascular morphogenesis.
• PKCε negatively regulates PVAT-derived vessel formation, linking metabolism to vasculogenesis.
• Dysregulation may contribute to tumor angiogenesis and retinopathies.
• Provides targets for therapeutic modulation of blood vessel growth.
• Essential for understanding epicardial-mesenchymal transformation during heart development.
• Relevant to tissue engineering and regenerative medicine approaches.
What Happens During negative regulation of vasculogenesis?
Inhibition of endothelial differentiation
In simple terms: Stopping precursor cells from becoming blood vessel cells.
Negative regulation of vasculogenesis can occur at the earliest stages by blocking the differentiation of angioblasts into mature endothelial cells. VEGF and Notch signaling are key pathways that control endothelial cell differentiation and arterial specification; their negative modulation can suppress the generation of new endothelial cells. For example, Notch signaling can restrict endothelial sprouting and differentiation, thereby limiting vasculogenic expansion. Additionally, VEGF receptor signal transduction is tightly regulated, and its inhibition reduces endothelial differentiation and lymphangiogenesis.
Repression of endothelial migration and tube formation
In simple terms: Preventing endothelial cells from moving and forming tubes.
Semaphorins are a family of guidance molecules that can negatively regulate vascular morphogenesis by inhibiting endothelial cell migration and tube formation. They act as repulsive cues that restrict where and when vessels form, ensuring proper patterning of the vascular network. This negative regulation is critical for avoiding excessive or misdirected vessel growth during development and in adult tissues.
Transcriptional control of angiogenic factors
In simple terms: Turning off genes that promote blood vessel growth.
Transcriptional cofactors can negatively regulate vasculogenesis by repressing pro-angiogenic genes. Med23, a subunit of the Mediator complex, supports angiogenesis and maintains vascular integrity through negative regulation of angiopoietin-2 expression. Angiopoietin-2 is a context-dependent regulator of endothelial quiescence and vessel stability; its repression by Med23 prevents excessive vascular permeability and sprouting. This illustrates how transcriptional mechanisms can restrain vasculogenic programs.
Metabolic and tissue-derived negative regulators
In simple terms: Signals from surrounding fat tissue can stop vessel formation.
Perivascular adipose tissue (PVAT) can influence vessel formation, and PKCε has been identified as a negative regulator of PVAT-derived vessel formation. This suggests that metabolic tissues can secrete factors or employ signaling pathways that inhibit vasculogenesis, linking energy homeostasis to vascular remodeling. Such tissue-specific negative regulation may be important in obesity and metabolic diseases where PVAT expands.
Negative regulation in heart development
In simple terms: Controlling vessel formation during heart development.
During avian heart development, positive and negative regulation of epicardial-mesenchymal transformation influences the formation of coronary vessels. Negative regulation of this process is essential for proper heart morphogenesis, and its disruption can lead to congenital heart defects. This highlights the importance of negative regulation of vasculogenesis in organ-specific contexts.
Key Genes Involved in GO:2001213 negative regulation of vasculogenesis
The following genes and proteins have been experimentally implicated in the negative regulation of vasculogenesis, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| SEMA3A | Semaphorin that inhibits endothelial cell migration and tube formation | Negative regulator of vascular morphogenesis |
| SEMA3F | Semaphorin with anti-angiogenic properties | Inhibits vasculogenesis in developing tissues |
| NOTCH1 | Receptor that restricts endothelial sprouting and differentiation | Modulates arterial specification and vasculogenesis |
| DLL4 | Notch ligand that negatively regulates endothelial sprouting | Controls vessel density and patterning |
| VEGFR2 | Receptor for VEGF; its negative modulation reduces endothelial differentiation | Target for inhibiting vasculogenesis |
| VEGFR1 | Decoy receptor that negatively regulates VEGF signaling | Modulates angiogenesis and lymphangiogenesis |
| MED23 | Mediator subunit that represses angiopoietin-2 expression | Maintains vascular integrity and negatively regulates angiogenesis |
| ANGPT2 | Angiopoietin-2; its repression supports vascular quiescence | Context-dependent regulator of endothelial stability |
| PRKCE | PKCε; negative regulator of PVAT-derived vessel formation | Links metabolism to vasculogenesis inhibition |
| HIF1A | Hypoxia-inducible factor; can indirectly suppress vasculogenesis under certain conditions | Regulates oxygen-dependent vascular remodeling |
| EPAS1 | Endothelial PAS domain protein 1; modulates VEGF signaling | Involved in endothelial differentiation |
| HEY1 | Notch target gene that represses endothelial sprouting | Negative regulator of angiogenesis |
| HEY2 | Notch target gene involved in arterial specification | Modulates vascular morphogenesis |
| NRP1 | Neuropilin-1; co-receptor for semaphorins and VEGF | Modulates both positive and negative regulation of vasculogenesis |
| PLXND1 | Plexin D1; receptor for semaphorins | Mediates repulsive cues in endothelial cells |
| CDH5 | VE-cadherin; maintains endothelial junctional integrity | Its regulation affects vascular stability |
| TEK | TIE2 receptor for angiopoietins | Modulates endothelial quiescence and vessel stability |
How Is negative regulation of vasculogenesis Regulated?
Negative regulation of vasculogenesis is controlled by a complex interplay of signaling pathways. VEGF and Notch signaling are central: VEGF receptor activation promotes endothelial differentiation, while Notch signaling downstream of DLL4 restricts sprouting and arterial specification, thereby negatively regulating vessel formation. Semaphorins provide repulsive guidance cues that inhibit endothelial migration and tube formation. Transcriptional regulation by Med23 represses angiopoietin-2, maintaining vascular integrity. Additionally, PKCε negatively regulates PVAT-derived vessel formation, linking metabolic signals to vasculogenesis inhibition. These pathways are modulated by oxygen tension, growth factors, and tissue-specific cues, ensuring balanced vascular development.
negative regulation of vasculogenesis and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| ANGPT2 | Progeria-associated vascular dysfunction | Patient-derived iPSC endothelial cells with ANGPT2 knockout or overexpression |
| SEMA3A | Tumor angiogenesis | Xenograft models with SEMA3A knockout or overexpression |
| PRKCE | Obesity-related vascular dysfunction | PVAT-derived vessel formation assays in PKCε knockout mice |
| MED23 | Vascular integrity disorders | Endothelial-specific Med23 knockout mice |
| NOTCH1 | Congenital vascular anomalies | Zebrafish or mouse models with Notch1 mutations |
Progeria and vascular dysfunction
In Hutchinson-Gilford progeria syndrome, vascular dysfunction is a hallmark, and angiopoietin-2 has been shown to reverse endothelial cell dysfunction in progeria vasculature. This suggests that negative regulation of vasculogenesis pathways involving angiopoietin-2 may be dysregulated in progeria, contributing to vascular pathology.
Cancer and tumor angiogenesis
Tumors often hijack vasculogenic programs to promote angiogenesis. Negative regulators such as semaphorins can inhibit tumor vessel formation, and their loss or downregulation is associated with increased tumor vascularization. Modulating negative regulation of vasculogenesis is therefore a potential anti-angiogenic strategy in cancer.
Metabolic disorders and PVAT
Perivascular adipose tissue (PVAT) influences vascular function, and PKCε acts as a negative regulator of PVAT-derived vessel formation. In obesity and metabolic syndrome, PVAT expands and may alter the balance of positive and negative regulators of vasculogenesis, contributing to vascular complications.
Developmental vascular anomalies
Disruption of negative regulation of vasculogenesis during heart development can lead to congenital vascular anomalies, as seen in studies of epicardial-mesenchymal transformation. Proper negative regulation is essential for coronary vessel patterning and heart morphogenesis.
From negative regulation of vasculogenesis-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X negatively regulate vasculogenesis? | Knockout of gene X in endothelial cells followed by tube formation assays |
| Does a point mutation in gene X affect its negative regulatory function? | Point-mutation knock-in of the mutation in cell lines or mice |
| Does overexpression of gene X inhibit vasculogenesis? | Overexpression of gene X in endothelial cells or transgenic mice |
| Does tagging gene X with a fluorescent protein affect its localization? | Knock-in of a fluorescent tag at the endogenous locus |
| Does gene X regulate angiopoietin-2 expression? | Knockout of gene X followed by ANGPT2 reporter assays |
| Does gene X modulate VEGF signaling? | Knockout or knockdown of gene X in VEGF-stimulated endothelial cells |
How to Study the negative regulation of vasculogenesis Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout screen | Loss-of-function effects on vasculogenesis | Identify negative regulators |
| RNA-seq | Transcriptional changes | Profile gene expression after negative regulator perturbation |
| Proteomics | Protein abundance and interactions | Discover complexes like Mediator |
| Tube formation assay | Endothelial network formation | Assess negative regulation in vitro |
| Migration assay | Endothelial cell motility | Evaluate semaphorin-mediated inhibition |
| Zebrafish vascular imaging | In vivo vessel patterning | Study developmental vasculogenesis |
| Mouse genetic models | Vascular phenotypes | Test gene function in vivo |
| Reporter assays | Promoter activity of target genes | Measure ANGPT2 repression by Med23 |
CRISPR knockout screens
Genome-wide CRISPR knockout screens can identify negative regulators of vasculogenesis by selecting for genes whose loss increases endothelial tube formation or vessel sprouting. Such screens have been used to uncover transcriptional cofactors like Med23 that repress pro-angiogenic factors.
RNA sequencing and transcriptomics
RNA-seq of endothelial cells under conditions that inhibit vasculogenesis can reveal gene expression changes driven by negative regulators. This approach helps identify downstream targets of pathways such as Notch and VEGF.
Proteomics and interactomics
Proteomic analysis can identify protein complexes involved in negative regulation, such as the Mediator complex containing Med23. Interactomics can reveal how negative regulators like semaphorins signal through plexin receptors.
Imaging and functional assays
Live-cell imaging of endothelial tube formation, sprouting, and migration can directly assess negative regulation of vasculogenesis. Zebrafish and mouse models allow visualization of vascular development in vivo.
How CRISPR Can Be Used to Study GO:2001213 negative regulation of vasculogenesis
Knockout
CRISPR knockout of candidate negative regulators can be used to test whether their loss increases vasculogenesis. For example, knocking out Med23 in endothelial cells may lead to increased angiopoietin-2 expression and enhanced vessel formation. Similarly, knocking out semaphorin genes could increase endothelial migration.
Point Mutation
Point mutations can be introduced to dissect specific domains or phosphorylation sites required for negative regulation. For instance, mutating key residues in Notch1 or VEGFR2 can alter their inhibitory functions in vasculogenesis.
Knock-in
Knock-in of reporter genes or tags allows visualization and tracking of negative regulators in vivo. Tagging endogenous Med23 with a fluorescent protein can reveal its dynamic localization during vessel formation.
Overexpression
Overexpression of negative regulators such as semaphorins or PKCε can suppress vasculogenesis in cell culture and animal models. This approach is useful for validating sufficiency of a candidate negative regulator.
How EDITGENE Supports negative regulation of vasculogenesis Research
Researchers studying negative regulation of vasculogenesis-related genes often need to determine whether a candidate gene is causally involved in restraining vessel formation. CRISPR-based models provide precise tools to manipulate these genes and assess their functional impact on endothelial differentiation, migration, and tube formation.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of vasculogenesis research.
Frequently Asked Questions About negative regulation of vasculogenesis
What is GO:2001213 negative regulation of vasculogenesis?
GO:2001213 is a Gene Ontology biological process term defined as any process that stops, prevents, or reduces the frequency, rate, or extent of vasculogenesis, the de novo formation of blood vessels from endothelial precursor cells.
What genes are involved in negative regulation of vasculogenesis?
Key genes include SEMA3A, SEMA3F, NOTCH1, DLL4, VEGFR1, MED23, ANGPT2, and PRKCE, among others.
How does Notch signaling negatively regulate vasculogenesis?
Notch signaling restricts endothelial sprouting and arterial specification, thereby limiting excessive vessel formation.
What is the role of semaphorins in vasculogenesis?
Semaphorins act as repulsive guidance cues that inhibit endothelial cell migration and tube formation, negatively regulating vascular morphogenesis.
How is negative regulation of vasculogenesis studied?
Researchers use CRISPR knockout screens, RNA-seq, proteomics, tube formation assays, and animal models such as zebrafish and mice.
What diseases are associated with dysregulated negative regulation of vasculogenesis?
Progeria, cancer, metabolic disorders, and congenital vascular anomalies have been linked to altered negative regulation of vasculogenesis.
Can CRISPR be used to study negative regulation of vasculogenesis?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models enable precise functional interrogation of candidate negative regulators.
What is the difference between vasculogenesis and angiogenesis?
Vasculogenesis is the de novo formation of blood vessels from angioblasts, while angiogenesis is the formation of new vessels from pre-existing ones; GO:2001213 specifically regulates vasculogenesis.
Which signaling pathways control negative regulation of vasculogenesis?
VEGF, Notch, semaphorin, and angiopoietin signaling pathways are major controllers of negative regulation of vasculogenesis.
How does Med23 negatively regulate vasculogenesis?
Med23, a Mediator subunit, represses angiopoietin-2 expression, thereby maintaining vascular integrity and negatively regulating angiogenesis.
Conclusion
Negative regulation of vasculogenesis (GO:2001213) is a critical biological process that restrains the de novo formation of blood vessels, ensuring proper vascular development and homeostasis. Key regulators include semaphorins, Notch signaling components, Med23, and PKCε, which act through diverse mechanisms to inhibit endothelial differentiation, migration, and tube formation. Dysregulation of this process is implicated in progeria, cancer, and metabolic disorders, making it a compelling area for therapeutic intervention. CRISPR-based models offer powerful tools to dissect the causal roles of specific genes in negative regulation of vasculogenesis. By combining knockout, point mutation, knock-in, and overexpression strategies with functional assays, researchers can uncover new regulatory mechanisms and identify targets for modulating vascular growth in disease.
References
- 2. Yang Y et al.. 2022. Med23 supports angiogenesis and maintains vascular integrity through negative regulation of angiopoietin2 expression.. Commun Biol 5(1):374 PMID: 35440711
- 3. Bussolino F et al.. 2006. Semaphoring vascular morphogenesis.. Endothelium 13(2):81-91 PMID: 16728327
- 4. Vakili S et al.. 2025. Angiopoietin-2 reverses endothelial cell dysfunction in progeria vasculature.. Aging Cell 24(2):e14375 PMID: 39422121
- 5. Morabito CJ et al.. 2001. Positive and negative regulation of epicardial-mesenchymal transformation during avian heart development.. Dev Biol 234(1):204-15 PMID: 11356030
- 6. Galli D et al.. 2015. PKCε is a negative regulator of PVAT-derived vessel formation.. Exp Cell Res 330(2):277-286 PMID: 25433270
- 7. Hirashima M. 2009. Regulation of endothelial cell differentiation and arterial specification by VEGF and Notch signaling.. Anat Sci Int 84(3):95-101 PMID: 19259767
- 8. Shibuya M et al.. 2006. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis.. Exp Cell Res 312(5):549-60 PMID: 16336962
