Unraveling the molecular mechanism of circLRP6 targeting miR-145 in intracranial aneurysm formation
Imagine the roads and highways within a bustling city suddenly developing weak spots that could collapse without warning. This scenario mirrors what happens in intracranial aneurysms (IAs)—weak bulges in brain artery walls that affect up to 3.2% of the population worldwide. When these bulges rupture, they cause a life-threatening type of stroke called subarachnoid hemorrhage, with devastating consequences: approximately 30% of patients die within 30 days, and a third of survivors experience severe disabilities 9 .
Worldwide prevalence of intracranial aneurysms
Mortality rate within 30 days of rupture
Survivors experience severe disabilities
For decades, researchers have tried to understand what causes these weak spots to form and rupture. While traditional risk factors like smoking, hypertension, and family history are well-known, the precise molecular mechanisms remained elusive. Recently, scientists have turned their attention to epigenetics—molecular switches that control gene activity without changing the DNA sequence itself. This exploration has revealed an intriguing molecular drama playing out within the cells of our blood vessels, centered on two key actors: circLRP6, a circular RNA molecule, and miR-145, a microRNA 1 9 . Their delicate balance appears to play a critical role in either maintaining vascular integrity or contributing to aneurysm development—a discovery that might eventually lead to new diagnostic tools and treatments for this silent threat.
Intracranial aneurysms represent one of neurology's most formidable challenges. These pathological dilatations of cerebral arteries don't typically cause symptoms until they rupture, making them particularly dangerous. The high mortality rate of ruptured IAs has driven scientists to investigate every aspect of their formation, from hemodynamic stresses to genetic predispositions 8 .
What makes IA research particularly complex is that it involves multiple cell types and biological processes. Vascular smooth muscle cells (VSMCs) that normally provide structural support to artery walls can change their behavior, switching from a "contractile" phenotype that maintains vessel tone to a "secretory" phenotype that contributes to wall weakening. Simultaneously, inflammation processes are activated, and the extracellular matrix—the scaffolding that holds cells together—begins to degrade 8 9 . These transformations gradually weaken the artery wall until it bulges outward, forming an aneurysm.
| Molecule | Type | Function in IA | Expression in IA |
|---|---|---|---|
| circLRP6 | Circular RNA | Acts as "sponge" for miR-145, protects vascular smooth muscle cells | Decreased 1 |
| miR-145 | MicroRNA | Promotes vascular smooth muscle cell transformation, inflammation | Increased 1 |
| α-SMA | Protein | Marker for contractile vascular smooth muscle cells | Decreased when circLRP6 low 1 |
| MMP-2, MMP-9 | Enzymes | Breakdown extracellular matrix, weakening vessel wall | Increased when circLRP6 low 1 |
Circular RNAs (circRNAs) represent a fascinating class of RNA molecules that form continuous loops instead of linear strands. This circular structure makes them remarkably stable and resistant to degradation compared to their linear counterparts, allowing them to persist longer in cells 6 .
Perhaps the most intriguing function of circRNAs is their ability to act as "molecular sponges" for microRNAs. By binding and sequestering specific microRNAs, circRNAs prevent them from interacting with their normal target genes, effectively acting as natural regulators of gene expression 6 .
On the other side of this molecular interaction is miR-145, a microRNA that has emerged as a master regulator of vascular smooth muscle cells. MicroRNAs are short RNA sequences that fine-tune gene expression by binding to complementary messenger RNAs 9 .
In healthy blood vessels, miR-145 helps maintain the contractile phenotype of VSMCs. However, under certain conditions, miR-145 can become overactive, pushing VSMCs to transition to a secretory phenotype that produces inflammatory molecules and matrix-degrading enzymes 1 .
Circular RNA molecule that acts as a molecular sponge
Sequesters miR-145
Prevents VSMC transformation and maintains vascular integrity
In 2024, researchers set out to test a compelling hypothesis: that circLRP6 acts as a natural sponge for miR-145 in the context of intracranial aneurysm formation. They proposed that when circLRP6 levels are sufficient, it sequesters miR-145, preventing it from promoting harmful changes in vascular smooth muscle cells. However, if circLRP6 levels drop, miR-145 becomes overactive, driving the cellular transformations that lead to aneurysm development 1 .
To test their hypothesis, the researchers designed a comprehensive study with multiple complementary approaches 1 :
Compared expression in aneurysm tissues vs. control arteries
Treated HBVSMCs with TNF-α to mimic aneurysm conditions
Overexpressed or knocked out circLRP6 in VSMCs
Measured proliferation, apoptosis, migration, and protein markers
The experiments yielded compelling results that painted a clear picture of the circLRP6-miR-145 relationship 1 :
| Parameter | Effect of circLRP6 | Effect of miR-145 |
|---|---|---|
| Expression in IA | Decreased | Increased |
| VSMC Proliferation | Inhibits | Promotes |
| VSMC Apoptosis | Promotes | Inhibits |
| VSMC Migration | Inhibits | Promotes |
| Contractile Proteins | Increases | Decreases |
| Inflammatory Response | Suppresses | Enhances |
Understanding complex molecular interactions like the circLRP6-miR-145 relationship requires sophisticated tools and techniques.
| Tool/Reagent | Function | Application in circLRP6 Study |
|---|---|---|
| RNase R Treatment | Enzyme that degrades linear RNAs but not circular RNAs | Isolated and confirmed circular nature of circLRP6 4 |
| TNF-α Stimulation | Inflammatory cytokine used to mimic aneurysm conditions | Created cellular model of IA in HBVSMCs 1 |
| qRT-PCR | Quantitative method to measure RNA expression levels | Detected expression levels of circLRP6 and miR-145 1 |
| siRNA/shRNA | Small RNAs designed to silence specific genes | Knocked down circLRP6 expression in VSMCs 1 |
| Overexpression Plasmids | DNA constructs that increase gene expression | Boosted circLRP6 levels in VSMCs 1 |
| Western Blot | Technique to detect specific proteins | Measured levels of α-SMA, SM22α, Calponin, etc. 1 |
| Flow Cytometry | Laser-based method to analyze cell characteristics | Assessed apoptosis rates in VSMCs 1 |
The discovery of the circLRP6-miR-145 axis opens up exciting new possibilities for diagnosing intracranial aneurysms. Since circRNAs are remarkably stable in biological fluids, they represent promising candidate biomarkers for identifying patients at high risk of aneurysm formation or rupture 9 .
A simple blood test that measures circLRP6 levels might one day help clinicians monitor aneurysm stability without invasive procedures.
Therapeutically, strategies to boost circLRP6 levels or activity in brain arteries could potentially slow or prevent aneurysm progression. While delivering RNA-based therapies to specific tissues remains challenging, advances in nanoparticle technology and viral vector design are rapidly overcoming these hurdles 6 .
Interestingly, the circLRP6-miR-145 relationship isn't unique to intracranial aneurysms—similar mechanisms have been observed in other vascular conditions, including atherosclerosis.
However, significant challenges remain. The complexity of epigenetic networks means that targeting a single molecule might have unforeseen consequences. Additionally, individual variations in genetic background and environmental exposures likely influence how the circLRP6-miR-145 axis functions in different patients 9 .
Future research will need to explore these interactions in more diverse populations and develop safe methods for delivering potential therapies to the appropriate cells in the cerebral arteries.
The emerging story of circLRP6 and miR-145 represents a microcosm of the complexity and elegance of biological systems. What initially appeared to be a simple relationship between two molecules has revealed itself as a sophisticated regulatory circuit that helps maintain the structural integrity of our brain's blood vessels. When this circuit breaks down—when circLRP6 levels fall and miR-145 activity rises—the stage is set for aneurysm formation.
This research exemplifies how exploring the once-dismissed "dark matter" of our genome—the non-coding RNAs that don't produce proteins—is revolutionizing our understanding of health and disease. The circLRP6-miR-145 axis represents just one of countless molecular conversations happening within our cells, but it provides powerful insights that might eventually lead to life-saving interventions for those at risk of intracranial aneurysms.
As research in this field progresses, we move closer to a future where we can not only better predict which aneurysms are dangerous but potentially stabilize them through targeted molecular therapies—all thanks to our growing understanding of the intricate tug-of-war between molecules like circLRP6 and miR-145.