GO:0035922 foramen ovale closure: Postnatal Cardiac Shunt Closure, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0035922 (foramen ovale closure) describes the morphogenetic process that shuts the fetal interatrial communication after birth, preventing right-to-left atrial blood flow.
• Incomplete closure produces a patent foramen ovale (PFO), a common residual shunt linked to cryptogenic stroke and migraine.
• Percutaneous device closure is the main clinical intervention for PFO and is supported by randomized trials for secondary stroke prevention.
• The process is driven by hemodynamic changes at birth, atrial septal remodeling, and tissue apposition rather than by a single enzyme.
• Post-closure atrial fibrillation is a recognized complication that shapes patient selection and follow-up.
• CRISPR knockout, knock-in, and overexpression models in cells and animals help dissect the genetic and molecular control of foramen ovale closure.
Description
The foramen ovale is a fetal interatrial opening that allows oxygenated blood to bypass the non-functional lungs by shunting from the right atrium to the left atrium. After birth, pulmonary circulation is established and left atrial pressure rises, triggering the morphogenetic process annotated as GO:0035922, foramen ovale closure, which seals this opening and separates the atrial chambers. Failure of this process leaves a patent foramen ovale (PFO), a common congenital remnant that can permit paradoxical embolism and is associated with cryptogenic stroke and migraine. Because PFO closure is now a guideline-supported intervention in selected patients, understanding the cellular and molecular events that normally close the foramen ovale has direct clinical relevance. Researchers study this process to identify genetic and signaling determinants of closure, to model incomplete closure, and to improve device-based and pharmacologic strategies.
foramen ovale closure At A Glance
| GO ID | GO:0035922 |
|---|---|
| GO term | foramen ovale closure |
| Ontology | biological_process |
| Synonym | foramen ovale of heart closure |
| Major function | Postnatal closure of the fetal interatrial communication to prevent right-to-left atrial blood flow |
| Anatomical site | Interatrial septum of the heart |
| Trigger | Hemodynamic changes and increased left atrial pressure after birth |
| Failure phenotype | Patent foramen ovale (PFO) with residual interatrial shunt |
| Clinical relevance | PFO is associated with cryptogenic stroke and migraine, and percutaneous closure is used for secondary prevention |
What Is GO:0035922?
GO:0035922 (foramen ovale closure) is the biological process by which the foramen ovale, the fetal interatrial communication, closes after birth so that blood no longer flows between the right and left atria. In the fetal heart, this opening is essential for directing oxygenated blood from the right atrium to the left atrium; after birth, changes in atrial pressure and septal tissue apposition lead to its functional and anatomical closure. The term encompasses the morphogenetic steps that seal the interatrial septum, and its failure results in a patent foramen ovale.
Why Is foramen ovale closure Important in Cell Biology?
Foramen ovale closure is important because it represents the normal postnatal transition from fetal to adult circulation, and its failure is one of the most common congenital cardiac remnants. A patent foramen ovale can serve as a conduit for paradoxical embolism, contributing to cryptogenic stroke, and has been linked to migraine with aura and other embolic phenomena. Understanding the mechanisms of closure informs patient selection for percutaneous closure, prediction of procedural outcomes, and management of complications such as post-closure atrial fibrillation.
• Defines the normal postnatal separation of the atrial chambers and completion of the fetal-to-neonatal circulatory transition.
• Failure of closure causes patent foramen ovale, a prevalent congenital cardiac finding.
• PFO is implicated in cryptogenic stroke through paradoxical embolism.
• PFO closure is a guideline-supported intervention for secondary stroke prevention in selected patients.
• PFO has been associated with migraine with aura, and closure may reduce migraine burden in some patients.
• Post-closure atrial fibrillation is a recognized complication influencing device selection and follow-up.
• Genetic and signaling determinants of closure are active areas of research using CRISPR and animal models.
• Understanding closure mechanisms supports development of less invasive and more durable closure strategies.
What Happens During foramen ovale closure?
Fetal foramen ovale and right-to-left shunting
In simple terms: Before birth, a small flap-like opening lets blood skip the lungs.
In the fetal heart, the foramen ovale is an essential interatrial communication that allows oxygenated blood returning from the placenta to pass from the right atrium to the left atrium, bypassing the non-aerated lungs. This right-to-left shunt is maintained by higher right atrial pressure and by the valve-like anatomy of the septum primum and septum secundum. The patency of this opening is a normal fetal adaptation rather than a pathological state.
Hemodynamic transition at birth
In simple terms: After birth, pressure changes push the flap shut.
With the onset of breathing, pulmonary vascular resistance falls and pulmonary blood flow increases, raising left atrial pressure relative to the right atrium. This reversal of the interatrial pressure gradient presses the septum primum against the septum secundum, functionally closing the foramen ovale. Persistent elevation of right atrial pressure or incomplete septal apposition can prevent functional closure and result in a patent foramen ovale.
Anatomical sealing and septal fusion
In simple terms: The flap eventually sticks and seals the hole.
Functional closure is followed by anatomical sealing, in which the overlapping septal tissue flaps fuse and the interatrial communication is obliterated. This morphogenetic step involves tissue apposition and remodeling of the interatrial septum, and it is the event captured by GO:0035922. Incomplete fusion leaves a residual slit-like or larger defect, which is the anatomical substrate of PFO.
Determinants of incomplete closure
In simple terms: Some people's flaps never fully seal, leaving a small tunnel.
Incomplete closure is influenced by septal anatomy, atrial size and pressure dynamics, and potentially by genetic factors affecting cardiac development. A PFO can remain clinically silent or become symptomatic when it permits paradoxical embolism. The presence of a PFO is common in the general population, but only a subset of individuals experience associated events such as cryptogenic stroke or migraine.
Clinical modulation of closure
In simple terms: Doctors can close the hole with a device if it causes problems.
When spontaneous closure fails and the PFO is implicated in disease, percutaneous device closure is used to mechanically seal the interatrial communication. Randomized evidence supports PFO closure for secondary prevention of cryptogenic stroke in selected patients, and suture-based and device-based techniques continue to evolve. Post-procedural atrial fibrillation is a recognized adverse event that requires surveillance and management.
Key Genes Involved in GO:0035922 foramen ovale closure
The genes and proteins below have been implicated in cardiac septation, atrial development, or clinical PFO-related phenotypes, and they represent candidate entry points for mechanistic studies of foramen ovale closure.
| Gene | Major Role | Research Relevance |
|---|---|---|
| NKX2-5 | Cardiac transcription factor regulating septation and conduction | Candidate for atrial septal defects and PFO-related phenotypes |
| GATA4 | Zinc-finger transcription factor in cardiac development | Associated with atrial septal defects and septal morphogenesis |
| TBX5 | T-box transcription factor in heart and limb development | Linked to atrial septation and conduction abnormalities |
| MYH6 | Atrial myosin heavy chain | Expressed in atria; relevant to atrial mechanics and septal function |
| ACTA2 | Smooth muscle actin | Contributes to septal tissue remodeling and vascular tone |
| COL1A1 | Type I collagen | Extracellular matrix component in septal fusion and remodeling |
| COL3A1 | Type III collagen | Matrix protein influencing tissue apposition and fusion |
| ELN | Elastin | Elastic fiber component in cardiac septa and vessels |
| FBN1 | Fibrillin-1 | Matrix protein with roles in cardiac connective tissue |
| NOTCH1 | Signaling receptor in cardiac development | Regulates valve and septal morphogenesis |
| BMP2 | Bone morphogenetic protein 2 | Signaling ligand in cardiac septation |
| BMP4 | Bone morphogenetic protein 4 | Involved in atrial and septal development |
| TBX20 | T-box transcription factor | Regulates cardiac chamber and septal development |
| PITX2 | Paired-like homeodomain transcription factor | Associated with atrial arrhythmia and atrial development |
| ZFPM2 | Zinc finger protein, FOG family member 2 | Cardiac transcription cofactor in septation |
| HAND2 | Heart and neural crest derivatives expressed 2 | Transcription factor in atrial and septal morphogenesis |
| MEF2C | Myocyte enhancer factor 2C | Regulates cardiac gene expression and development |
| SRF | Serum response factor | Controls cardiac structural gene expression |
How Is foramen ovale closure Regulated?
Foramen ovale closure is regulated primarily by hemodynamic forces and developmental signaling rather than by a single molecular switch. The fall in pulmonary vascular resistance and rise in left atrial pressure after birth provide the mechanical trigger for flap apposition. Cardiac transcription factors such as NKX2-5, GATA4, and TBX5, together with signaling pathways including NOTCH and BMP, shape the septal structures that determine whether closure is complete. Incomplete closure may also be influenced by atrial arrhythmia substrates, as suggested by the association between PFO closure and post-procedural atrial fibrillation.
foramen ovale closure and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| NKX2-5 | Atrial septal defects and conduction disease | Knockout or knock-in mouse; iPSC-derived cardiomyocytes |
| GATA4 | Atrial septal defects | Cardiac-specific knockout mouse; patient-derived iPSCs |
| TBX5 | Holt-Oram syndrome with septal defects | Knockout mouse; iPSC-derived atrial cells |
| PITX2 | Atrial fibrillation susceptibility | Knockout mouse; atrial cardiomyocyte models |
| NOTCH1 | Valve and septal malformations | Conditional knockout mouse; zebrafish |
Patent foramen ovale and cryptogenic stroke
Failure of foramen ovale closure leaves a patent foramen ovale, which can permit paradoxical embolism and is strongly associated with cryptogenic stroke, particularly in younger patients without other identified causes. Randomized trials have shown that percutaneous PFO closure reduces recurrent stroke risk in selected patients compared with medical therapy alone. Patient selection, device choice, and adjunctive antithrombotic therapy remain active areas of investigation.
Migraine with aura
PFO has been associated with migraine with aura, and observational and randomized data suggest that closure may reduce migraine frequency in some patients. The mechanism is thought to involve paradoxical embolization of vasoactive substances or microemboli that bypass pulmonary filtration. However, the role of closure in migraine management remains debated and is not universally recommended.
Atrial fibrillation after closure
Atrial fibrillation is a recognized complication after percutaneous PFO closure, with incidence varying by device type, patient age, and follow-up duration. Proposed mechanisms include device-related atrial irritation, altered atrial mechanics, and pre-existing atrial substrate. Management includes surveillance, rate or rhythm control, and in some cases anticoagulation, balancing stroke risk against bleeding.
Other embolic and decompression-related conditions
PFO has been implicated in other embolic phenomena, including decompression sickness in divers and platypnea-orthodeoxia syndrome, where right-to-left shunting causes hypoxemia in the upright position. Closure may be considered in selected symptomatic patients, though evidence is less robust than for cryptogenic stroke.
From foramen ovale closure-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of a candidate gene prevent foramen ovale closure? | CRISPR knockout in mouse or iPSC-derived atrial cells |
| Does a patient variant impair septal fusion? | CRISPR point mutation knock-in in iPSCs or mouse |
| Can a reporter track septal cell lineages? | Tagged knock-in reporter at an endogenous locus |
| Does overexpression of a signaling factor alter closure? | Transgenic or viral overexpression in cardiac tissue |
| Which pathways regulate septal remodeling? | CRISPR library screening in cardiac progenitor cells |
| Can device or suture closure be modeled in vitro? | Explant or microphysiological interatrial septum models |
How to Study the foramen ovale closure Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Echocardiography with saline contrast | Presence and severity of interatrial shunt | PFO diagnosis and closure follow-up |
| Transcranial Doppler | Right-to-left shunting | Screening for paradoxical embolism |
| CRISPR knockout in mouse | Requirement of a gene for septal closure | Candidate gene validation |
| CRISPR knock-in of patient variants | Functional impact of a variant | Variant interpretation in PFO |
| Single-cell RNA sequencing | Cell types and states in the septum | Mapping closure-associated programs |
| Chromatin accessibility assays | Regulatory element activity | Defining transcription factor networks |
| CRISPR library screening | Novel regulators of septal development | Discovery of closure pathways |
| Clinical registries and trials | Stroke recurrence and complication rates | Evaluating closure outcomes |
Genetic and genomic approaches
CRISPR knockout, knock-in, and overexpression in cell and animal models allow direct testing of candidate genes for their role in septal development and foramen ovale closure. Transcriptomic profiling of atrial and septal tissues can identify pathways enriched during closure, and CRISPR library screens can nominate novel regulators. These approaches help distinguish causal genes from bystander associations in PFO cohorts.
Imaging and functional assessment
Echocardiography, including transthoracic and transesophageal approaches, is central to diagnosing PFO and assessing shunt severity and septal anatomy. Agitated saline contrast studies and transcranial Doppler can detect right-to-left shunting and guide clinical decision-making. In animal models, high-resolution ultrasound and micro-CT can track closure dynamics and septal morphology.
Molecular and cellular assays
Immunohistochemistry, in situ hybridization, and single-cell RNA sequencing can map the cell types and signaling states in the interatrial septum during closure. Protein interaction and chromatin accessibility assays can define regulatory networks involving NKX2-5, GATA4, and TBX5. These methods link candidate genes to the morphogenetic steps of GO:0035922.
Clinical and translational research
Randomized controlled trials and registries provide evidence on PFO closure outcomes, including stroke recurrence and atrial fibrillation risk. Device and suture-based closure techniques are compared in state-of-the-art reviews and clinical studies. Translational research integrates genetic, imaging, and procedural data to refine patient selection.
How CRISPR Can Be Used to Study GO:0035922 foramen ovale closure
Knockout
CRISPR knockout of candidate genes such as NKX2-5, GATA4, or TBX5 in mouse models or iPSC-derived atrial cells can test whether loss of function impairs foramen ovale closure and produces septal defects. Knockout studies help establish causality and reveal compensatory pathways that may mask phenotypes.
Point Mutation
CRISPR point mutation knock-in can recreate patient-specific variants in endogenous loci to assess their impact on septal morphogenesis and closure. This approach is valuable for variants of uncertain significance identified in PFO or atrial septal defect cohorts.
Knock-in
Tagged knock-in reporters, such as fluorescent or epitope-tagged alleles, allow lineage tracing and protein localization studies in the developing interatrial septum. Knock-in of regulatory elements can also test enhancer function during closure.
Overexpression
CRISPR activation or transgenic overexpression can test whether increased dosage of a signaling factor, such as BMP2 or NOTCH1, alters septal remodeling and closure. Overexpression models complement loss-of-function studies and can reveal dosage-sensitive mechanisms.
How EDITGENE Supports foramen ovale closure Research
Researchers studying foramen ovale closure-related genes often need to determine whether a candidate gene is causally involved in septal morphogenesis or merely associated with PFO in patient cohorts. Rigorous functional validation requires precise genome editing, controlled expression, and scalable screening in relevant cardiac cell and animal models.
Contact EDITGENE today to design your custom CRISPR model for foramen ovale closure research.
Frequently Asked Questions About foramen ovale closure
What is foramen ovale closure (GO:0035922)?
It is the biological process by which the fetal interatrial opening closes after birth, preventing blood flow between the right and left atria.
What genes are involved in foramen ovale closure?
Genes implicated in cardiac septation and atrial development include NKX2-5, GATA4, TBX5, NOTCH1, BMP2, and BMP4, among others.
Why does the foramen ovale fail to close?
Incomplete closure can result from septal anatomy, pressure dynamics, and genetic factors affecting cardiac development, leading to a patent foramen ovale.
What is a patent foramen ovale (PFO)?
A PFO is a persistent interatrial communication caused by failure of foramen ovale closure, which can permit paradoxical embolism.
How is PFO diagnosed?
Echocardiography with saline contrast and transcranial Doppler are commonly used to detect right-to-left shunting and assess septal anatomy.
Does PFO closure prevent stroke?
Randomized trials support percutaneous PFO closure for secondary prevention of cryptogenic stroke in selected patients.
What are the risks of PFO closure?
Atrial fibrillation is a recognized complication after percutaneous closure, requiring surveillance and management.
Can CRISPR be used to study foramen ovale closure?
Yes, CRISPR knockout, knock-in, and overexpression models in cardiac cells and animals can test candidate gene function in septal morphogenesis.
What research methods are used for foramen ovale closure?
Methods include echocardiography, single-cell RNA sequencing, chromatin accessibility assays, and CRISPR library screening.
Is PFO closure recommended for migraine?
Observational and randomized data suggest possible migraine benefit, but closure is not universally recommended for migraine alone.
Conclusion
GO:0035922 (foramen ovale closure) captures the essential postnatal morphogenetic process that separates the atrial chambers and completes the transition from fetal to adult circulation. Its failure underlies patent foramen ovale, a common condition linked to cryptogenic stroke, migraine, and other embolic phenomena. Clinical management has advanced through percutaneous closure, yet questions remain about patient selection, complications such as atrial fibrillation, and the genetic determinants of closure. Continued research using CRISPR models, imaging, and multi-omic approaches will refine our understanding of this process and improve outcomes for patients with PFO.
References
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- 2. Giblett JP et al.. 2020. Patent Foramen Ovale Closure: State of the Art.. Interv Cardiol 15:e15 PMID: 33318751
- 3. Devos P et al.. 2023. Patent Foramen Ovale Percutaneous Closure: Evolution and Ongoing Challenges.. J Clin Med 13(1) PMID: 38202061
- 4. Alkhouli M et al.. 2019. Patent foramen ovale closure for secondary stroke prevention.. Eur Heart J 40(28):2339-2350 PMID: 30957864
- 5. Cannata F et al.. 2024. Percutaneous suture-based patent foramen ovale closure: A state-of-the-art review.. Trends Cardiovasc Med 34(6):404-413 PMID: 37931791
- 6. Gonnah AR et al.. 2022. Patent foramen ovale: diagnostic evaluation and the role of device closure.. Clin Med (Lond) 22(5):441-448 PMID: 36507808
- 7. Randhawa S et al.. 2024. Percutaneous Patent Foramen Ovale Closure: Stroke and Beyond.. Curr Cardiol Rev 20(3):77-86 PMID: 38485682
- 8. Apostolos A et al.. 2024. Atrial Fibrillation After Patent Foramen Ovale Closure: Incidence, Pathophysiology, and Management.. J Am Heart Assoc 13(9):e034249 PMID: 38639354
