GO:0110081 negative regulation of placenta blood vessel development: Angiogenesis Restraint, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0110081 describes any biological process that stops, prevents, or reduces the frequency, rate, or extent of blood vessel development in the placenta.
• Placental angiogenesis is a tightly balanced process; excessive or insufficient vessel formation both impair fetal-maternal exchange and pregnancy outcome.
• Endoglin (ENG) is a major regulator of placental vascular development, and its dysregulation is linked to pre-eclampsia and related disorders.
• Hypoxia-inducible factor 1 alpha (HIF1A) and SOX9 expression patterns in placental tissue are altered in HELLP syndrome, a severe pregnancy complication.
• Sirtuin 1 (SIRT1) deficiency in trophoblasts impairs placental function and contributes to pre-eclampsia pathogenesis.
• Assisted reproductive technologies and in vitro embryo production can introduce errors in placental vascular development, providing models to study negative regulation.
Description
The Gene Ontology term GO:0110081, negative regulation of placenta blood vessel development, defines any process that stops, prevents, or reduces the frequency, rate, or extent of blood vessel development in the placenta. This biological process is essential for normal pregnancy because the placenta requires a carefully controlled vascular network to support fetal growth and maternal-fetal exchange. Disruption of this balance can lead to serious complications such as pre-eclampsia, HELLP syndrome, and fetal growth restriction. Researchers study this term to understand how molecular signals restrain angiogenesis in the placenta, and how failures in this restraint contribute to disease. The process involves a complex interplay of growth factors, receptors, transcription factors, and epigenetic regulators that collectively determine vascular density and function in placental tissues. Because placental vascular development is sensitive to environmental and genetic perturbations, it serves as a valuable model for studying both normal and pathological angiogenesis.
negative regulation of placenta blood vessel development At A Glance
| GO ID | GO:0110081 |
|---|---|
| GO term | negative regulation of placenta blood vessel development |
| Ontology | biological_process |
| Synonym | none |
| Major function | Restrains the formation and growth of blood vessels in the placenta to maintain proper vascular density and function |
| Related process | placenta blood vessel development (GO:0060674) |
| Regulatory direction | Negative (inhibitory) |
| Key tissues | Placenta, trophoblast, umbilical vessels |
| Disease relevance | Pre-eclampsia, HELLP syndrome, fetal growth restriction |
What Is GO:0110081?
GO:0110081 is a biological process term that describes any mechanism that negatively regulates the development of blood vessels in the placenta. It encompasses molecular events that inhibit endothelial cell proliferation, migration, tube formation, or vessel maturation within placental tissues, thereby reducing the overall extent or rate of placental angiogenesis.
Why Is negative regulation of placenta blood vessel development Important in Cell Biology?
Understanding negative regulation of placenta blood vessel development is critical because an imbalance in placental angiogenesis underlies major pregnancy disorders such as pre-eclampsia and HELLP syndrome, which affect both mother and fetus. The placenta is the sole interface for nutrient and gas exchange, and its vascular network must be precisely controlled; excessive or insufficient vessel formation can lead to placental insufficiency, fetal hypoxia, and intrauterine growth restriction. Moreover, placental vascular development shares molecular pathways with tumor angiogenesis, making it a valuable model for studying angiogenesis regulators. Research into this process also informs assisted reproductive technologies, where in vitro manipulation can alter placental vascular gene expression and methylation. Thus, GO:0110081 provides a framework for investigating how inhibitory signals maintain placental vascular homeostasis and how their failure contributes to disease.
• Placental vascular development is essential for fetal growth; its negative regulation prevents excessive or disorganized angiogenesis.
• Dysregulation of negative regulators like endoglin is associated with pre-eclampsia and HELLP syndrome.
• SIRT1 deficiency in trophoblasts impairs placental function and is implicated in pre-eclampsia pathogenesis.
• Hypoxia and stress conditions alter the expression of transcription factors such as HIF1A and SOX9 in placental tissues.
• Assisted reproductive technologies can induce epigenetic changes in placental genes related to vascular development.
• Animal models of in vitro embryo production show errors in placental vascular development, offering insights into negative regulation.
• The process is a useful comparative model for understanding angiogenesis inhibitors in cancer research.
• Antibodies targeting marinobufagenin can reverse placenta-induced fibrosis in umbilical arteries, linking vascular regulation to pregnancy complications.
• Studying this term helps identify biomarkers for pregnancy disorders and potential therapeutic targets.
• It provides a basis for developing CRISPR models to dissect gene function in placental angiogenesis.
What Happens During negative regulation of placenta blood vessel development?
Inhibition of pro-angiogenic signaling
In simple terms: This step blocks the signals that tell blood vessels to grow.
Negative regulation of placenta blood vessel development often involves interfering with pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and its receptors. Endoglin, a co-receptor for TGF-beta family ligands, modulates VEGF signaling and is highly expressed in the placenta; its altered function can inhibit endothelial cell proliferation and migration. VEGF receptor signal transduction pathways are central to angiogenesis, and their negative regulation can suppress vessel formation. In pre-eclampsia, elevated levels of soluble endoglin sequester VEGF and reduce its availability, thereby inhibiting placental angiogenesis.
Transcriptional and hypoxia-driven control
In simple terms: This step involves gene switches that respond to low oxygen and stress.
Hypoxia-inducible factor 1 alpha (HIF1A) is a key transcription factor that regulates genes involved in angiogenesis. In placentas from patients with HELLP syndrome, HIF1A and SOX9 expression patterns are altered, suggesting that transcriptional control contributes to negative regulation of placental vessel development under pathological conditions. Stress-induced changes in nucleocytoplasmic localization of transcription factors can further modulate gene expression programs that restrain angiogenesis.
Epigenetic and metabolic regulation
In simple terms: This step changes how genes are read without changing the DNA code.
Epigenetic mechanisms, including DNA methylation, can influence the expression of genes that negatively regulate placental angiogenesis. Placentas derived from assisted reproductive technology show genome-wide DNA methylation and gene expression changes, some of which affect vascular development pathways. Sirtuin 1 (SIRT1), a NAD+-dependent deacetylase, regulates trophoblast function; its deficiency leads to impaired placental development and pre-eclampsia-like features, indicating a role in negative regulation of vessel development.
Extracellular matrix and vascular remodeling
In simple terms: This step involves the material around blood vessels that can stop them from growing.
The extracellular matrix and factors such as marinobufagenin can influence placental vascular remodeling. Antibodies against marinobufagenin reverse placenta-induced fibrosis of umbilical arteries in pre-eclampsia, suggesting that this pathway contributes to negative regulation of vessel development and vascular stiffness. In vitro-produced bovine embryos often show errors in placental vascular development, providing a model to study how extracellular cues restrict angiogenesis.
Key Genes Involved in GO:0110081 negative regulation of placenta blood vessel development
The following genes and proteins have been implicated in the negative regulation of placenta blood vessel development based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| ENG | TGF-beta co-receptor; modulates VEGF signaling and endothelial cell behavior | Altered in pre-eclampsia; soluble endoglin inhibits placental angiogenesis |
| HIF1A | Hypoxia-inducible transcription factor regulating angiogenic genes | Expression changes in HELLP syndrome placentas |
| SOX9 | Transcription factor involved in developmental processes | Altered expression in HELLP placentas |
| SIRT1 | NAD+-dependent deacetylase regulating trophoblast function | Deficiency impairs placental development and links to pre-eclampsia |
| VEGFA | Key pro-angiogenic growth factor | Negatively regulated to control placental vessel development |
| KDR (VEGFR2) | VEGF receptor mediating angiogenic signals | Target of negative regulation in placenta |
| FLT1 | VEGF receptor that can sequester VEGF | Soluble FLT1 contributes to anti-angiogenic state in pre-eclampsia |
| MBG | Marinobufagenin, a cardiotonic steroid | Involved in placenta-induced fibrosis; antibody reverses effects |
| CDH5 | Vascular endothelial cadherin, endothelial junction protein | Marker of vessel development; may be affected by negative regulation |
| PECAM1 | Endothelial cell adhesion molecule | Used to assess vessel density in placenta |
| MMP2 | Matrix metalloproteinase involved in vascular remodeling | May be regulated to inhibit vessel development |
| MMP9 | Matrix metalloproteinase involved in vascular remodeling | May be regulated to inhibit vessel development |
| TGFB1 | Transforming growth factor beta, regulates endothelial cells | Signaling through endoglin affects placental angiogenesis |
| ACVR1 | Activin receptor-like kinase, TGF-beta family receptor | Part of endoglin signaling complex in placenta |
| NOS3 | Endothelial nitric oxide synthase | Regulates vascular tone and angiogenesis; may be negatively regulated |
| EPAS1 | Hypoxia-inducible factor 2 alpha | Contributes to hypoxia response in placenta |
| HAND1 | Transcription factor in trophoblast development | May influence placental vascular development |
How Is negative regulation of placenta blood vessel development Regulated?
The negative regulation of placenta blood vessel development is controlled by a network of signaling pathways, including TGF-beta/endoglin, VEGF/VEGFR, and hypoxia-sensing mechanisms. Endoglin modulates TGF-beta signaling to influence endothelial cell proliferation and migration, and its soluble form acts as a decoy for VEGF, reducing angiogenesis. Hypoxia-inducible factors such as HIF1A and EPAS1 respond to low oxygen and can either promote or restrain vessel growth depending on context. SIRT1, a metabolic sensor, regulates trophoblast differentiation and function, and its loss leads to impaired placental vascularization. Epigenetic modifications, including DNA methylation, can stably alter the expression of angiogenic regulators in response to assisted reproductive technologies. Additionally, stress-induced nucleocytoplasmic shuttling of transcription factors can dynamically modulate gene expression programs that inhibit angiogenesis.
negative regulation of placenta blood vessel development and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| ENG | Pre-eclampsia; anti-angiogenic state | Knockout or overexpression of soluble ENG in trophoblast cell lines |
| HIF1A | HELLP syndrome; hypoxia response | Point mutation to stabilize HIF1A in placental cells |
| SIRT1 | Pre-eclampsia; trophoblast dysfunction | Knockout SIRT1 in trophoblast cells or organoids |
| FLT1 | Pre-eclampsia; VEGF sequestration | Overexpression of soluble FLT1 in placental models |
| MBG | Umbilical artery fibrosis | Antibody treatment in explant cultures |
Pre-eclampsia and HELLP syndrome
Pre-eclampsia is a pregnancy-specific disorder characterized by hypertension and proteinuria, often associated with placental vascular dysfunction. Elevated soluble endoglin and altered TGF-beta signaling contribute to an anti-angiogenic state that impairs placental blood vessel development. In HELLP syndrome, a severe form of pre-eclampsia, expression of SOX9 and HIF1A is altered in placental tissues, suggesting that transcriptional dysregulation of negative regulators plays a role in disease pathogenesis. SIRT1 deficiency in trophoblasts also promotes pre-eclampsia-like features, linking metabolic regulation to placental vascular restraint.
Fetal growth restriction and placental insufficiency
Insufficient placental angiogenesis can lead to fetal growth restriction due to inadequate nutrient and oxygen supply. Negative regulation of vessel development, when excessive, may contribute to placental insufficiency. In vitro-produced bovine embryos often exhibit errors in placental vascular development, providing a model for studying how aberrant negative regulation affects fetal growth. Assisted reproductive technologies can induce epigenetic changes in placental genes, potentially affecting vascular development and fetal outcomes.
Umbilical artery fibrosis and vascular remodeling
Placenta-induced fibrosis of umbilical arteries is observed in pre-eclampsia, and marinobufagenin has been implicated in this process. Antibodies against marinobufagenin can reverse fibrosis, suggesting that targeting negative regulators of vessel development may have therapeutic potential. This highlights the interplay between placental factors and vascular remodeling in pregnancy complications.
From negative regulation of placenta blood vessel development-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X negatively regulate placental angiogenesis? | Knockout of gene X in trophoblast cell line (e.g., HTR-8/SVneo) followed by tube formation assay |
| Does a specific point mutation in gene Y alter its anti-angiogenic function? | Point mutation knock-in in placental cells using CRISPR |
| Does overexpression of gene Z inhibit vessel development? | Overexpression of gene Z in trophoblast cells and co-culture with endothelial cells |
| How does epigenetic regulation affect negative regulators? | DNA methylation editing or treatment with methylation inhibitors in placental cells |
| What is the role of a candidate gene in vivo? | Knockout mouse models with placental-specific deletion |
| Can a tagged protein reveal localization dynamics? | Tagged knock-in of gene of interest in trophoblast cells for imaging |
How to Study the negative regulation of placenta blood vessel development Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Global gene expression changes | Identify negative regulators altered in pre-eclampsia |
| DNA methylation array | Epigenetic modifications | Assess impact of ART on placental vascular genes |
| Tube formation assay | Endothelial cell network formation | Test anti-angiogenic effect of candidate genes |
| Western blot | Protein expression and phosphorylation | Validate signaling changes in TGF-beta/VEGF pathways |
| Immunohistochemistry | Vessel density and marker localization | Compare placental tissues from normal and pathological pregnancies |
| Co-immunoprecipitation | Protein-protein interactions | Study endoglin-containing receptor complexes |
| Proximity ligation assay | In situ protein interactions | Visualize signaling complexes in placental cells |
| Live-cell imaging | Dynamic protein localization | Track transcription factor shuttling under stress |
Transcriptomic and epigenomic profiling
RNA sequencing (RNA-seq) and DNA methylation arrays can identify genes and pathways involved in negative regulation of placenta blood vessel development. Studies using these methods have revealed altered expression of ENG, HIF1A, and SIRT1 in pathological placentas. These approaches help pinpoint candidate regulators and epigenetic marks associated with disease.
Functional assays for angiogenesis
In vitro tube formation assays, endothelial cell migration assays, and spheroid sprouting assays are used to measure the effects of candidate genes on vessel development. For example, manipulating endoglin levels in trophoblast cells affects endothelial tube formation. These assays provide direct functional evidence for negative regulation.
Protein interaction and signaling studies
Co-immunoprecipitation, Western blotting, and proximity ligation assays can dissect signaling pathways involving endoglin, TGF-beta receptors, and VEGF receptors. These methods reveal how negative regulators interfere with pro-angiogenic signaling at the protein level.
Imaging and histological analysis
Immunohistochemistry and immunofluorescence for endothelial markers such as CDH5 and PECAM1 allow visualization of placental vessel density and architecture. Imaging of tagged proteins in live cells can reveal dynamic localization of negative regulators.
How CRISPR Can Be Used to Study GO:0110081 negative regulation of placenta blood vessel development
Knockout
CRISPR knockout of candidate negative regulators such as ENG or SIRT1 in trophoblast cell lines can reveal their role in restraining placental angiogenesis. For example, knocking out SIRT1 in trophoblasts impairs placental function and mimics pre-eclampsia features. Knockout models allow researchers to assess whether loss of a gene enhances vessel development, confirming its negative regulatory function.
Point Mutation
Introducing specific point mutations in genes like HIF1A can stabilize or alter its activity, mimicking disease-associated variants. Such models help dissect how subtle changes in negative regulators affect placental vascular development. Point mutations can also be used to study phosphorylation sites or interaction domains in endoglin.
Knock-in
Knock-in of tagged versions of proteins (e.g., GFP-ENG) allows visualization of their localization and dynamics in placental cells. This approach can reveal how negative regulators traffic within trophoblasts and interact with signaling partners. Knock-in of disease-relevant mutations can also model genetic contributions to pre-eclampsia.
Overexpression
Overexpression of soluble endoglin or other anti-angiogenic factors in placental cells can recapitulate the anti-angiogenic state of pre-eclampsia. Such models are useful for testing whether increased levels of a negative regulator are sufficient to inhibit placental vessel development. Overexpression can also be used to study downstream signaling changes.
How EDITGENE Supports negative regulation of placenta blood vessel development Research
Researchers studying negative regulation of placenta blood vessel development-related genes often need to determine whether a candidate gene is causally involved in restraining angiogenesis or is merely a bystander. EDITGENE provides a comprehensive suite of CRISPR-based services to enable precise genetic manipulation in placental cell models, from knockout to knock-in, allowing functional validation of candidate regulators.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of placenta blood vessel development research.
Frequently Asked Questions About negative regulation of placenta blood vessel development
What is GO:0110081?
GO:0110081 is a Gene Ontology term for negative regulation of placenta blood vessel development, describing any process that stops, prevents, or reduces the frequency, rate, or extent of blood vessel development in the placenta.
What genes are involved in negative regulation of placenta blood vessel development?
Key genes include ENG (endoglin), HIF1A, SOX9, SIRT1, VEGFA, FLT1, and MBG, among others, as reported in studies of placental pathology.
How is placenta blood vessel development negatively regulated?
It is regulated by anti-angiogenic factors such as soluble endoglin, by hypoxia-driven transcription factors like HIF1A, and by epigenetic and metabolic regulators such as SIRT1.
Why is negative regulation of placenta blood vessel development important?
Proper control of placental angiogenesis is essential for fetal growth; its dysregulation is linked to pre-eclampsia, HELLP syndrome, and fetal growth restriction.
What diseases are associated with abnormal negative regulation of placenta blood vessel development?
Pre-eclampsia, HELLP syndrome, fetal growth restriction, and umbilical artery fibrosis are associated with altered regulation of placental angiogenesis.
How can CRISPR be used to study negative regulation of placenta blood vessel development?
CRISPR knockout, point mutation, knock-in, and overexpression models allow functional testing of candidate genes in trophoblast and endothelial cells to determine their role in restraining angiogenesis.
What cell models are used to study placental angiogenesis?
Common models include HTR-8/SVneo trophoblast cells, primary trophoblasts, and endothelial cells in co-culture, as well as animal models such as knockout mice.
What is the role of endoglin in placenta blood vessel development?
Endoglin is a TGF-beta co-receptor that modulates VEGF signaling; its soluble form acts as an anti-angiogenic factor and is elevated in pre-eclampsia.
How does SIRT1 affect placental blood vessel development?
SIRT1 deficiency in trophoblasts impairs placental function and contributes to pre-eclampsia pathogenesis, indicating a role in negative regulation of vessel development.
What methods are used to study negative regulation of placenta blood vessel development?
Methods include RNA-seq, DNA methylation arrays, tube formation assays, Western blotting, immunohistochemistry, and CRISPR-based genetic manipulation.
Conclusion
GO:0110081, negative regulation of placenta blood vessel development, is a critical biological process that maintains placental vascular homeostasis. Its dysregulation is implicated in major pregnancy disorders such as pre-eclampsia and HELLP syndrome, making it a key area of research. Advances in CRISPR gene editing and functional genomics now allow precise dissection of the molecular players involved, offering hope for new therapeutic strategies. EDITGENE provides the tools and expertise to accelerate this research.
References
- 1. Gregory AL et al.. 2014. Review: the enigmatic role of endoglin in the placenta.. Placenta 35 Suppl:S93-9 PMID: 24252708
- 2. Akalın SA et al.. 2023. Role of SOX9 and Hif-1α expression in placentas of patients with HELLP.. Acta Cir Bras 38:e388023 PMID: 37878989
- 3. Farin PW et al.. 2006. Errors in development of fetuses and placentas from in vitro-produced bovine embryos.. Theriogenology 65(1):178-91 PMID: 16266745
- 4. Yu H et al.. 2023. Effects of sirtuin 1 deficiency on trophoblasts and its implications in the pathogenesis of pre-eclampsia.. J Obstet Gynaecol 43(2):2282103 PMID: 37966393
- 5. Auvinen P et al.. 2024. Genome-wide DNA methylation and gene expression in human placentas derived from assisted reproductive technology.. Commun Med (Lond) 4(1):267 PMID: 39702541
- 6. Fedorova OV et al.. 2018. Antibody to Marinobufagenin Reverses Placenta-Induced Fibrosis of Umbilical Arteries in Preeclampsia.. Int J Mol Sci 19(8) PMID: 30104471
- 7. 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
- 8. Khamit A et al.. 2024. Stress-Induced Changes in Nucleocytoplasmic Localization of Crucial Factors in Gene Expression Regulation.. Int J Mol Sci 25(7) PMID: 38612704
