Molecular-genetic mechanisms of cerebral arteriovenous malformations: a systematic review of germline, somatic and experimental evidence

Inside the human brain, a complex network of blood vessels delivers oxygen and nutrients to every cell. Normally, arteries carry blood under high pressure to tiny capillaries, where the pressure drops and exchange happens, before the blood flows into veins. A cerebral arteriovenous malformation is a dangerous shortcut in this system. It is a tangle of vessels where arteries connect directly to veins, bypassing the protective capillary bed entirely. This creates a high-pressure rush of blood that the thin-walled veins are not built to handle. Over time, this constant stress reshapes the vessel walls and significantly increases the risk of rupture, leading to a brain hemorrhage. For decades, doctors viewed these malformations as random accidents of development, appearing sporadically in people with no family history. However, a new understanding is emerging, revealing that these lesions are not merely random but are driven by specific, identifiable errors in the genetic instructions that tell blood vessels how to form and mature.

A team of researchers from the Burdenko Neurosurgery Institute and other institutions in Russia set out to map the molecular blueprint behind these brain malformations. They conducted a systematic review, gathering and analyzing evidence from dozens of studies published up to early 2026. Their goal was to connect the dots between inherited genetic conditions, random genetic mutations that occur after birth, and the biological pathways that go wrong to create these dangerous tangles. By bringing together human genetic data, laboratory experiments, and animal models, they aimed to create a clear picture of why these malformations form and what might be done to stop them.

The researchers found that the story of these malformations is actually two stories happening at once. In some cases, the problem starts before a person is born. These individuals inherit a genetic variant from a parent that weakens the body's ability to build strong, stable blood vessels. The most common of these inherited conditions involve genes like ENG and ACVRL1, which act as part of a signaling system that tells blood vessels when to stop growing and when to strengthen their walls. When these genes are faulty, the vessels remain fragile and prone to forming shortcuts. Another inherited group involves genes like RASA1 and EPHB4, which help decide whether a vessel becomes an artery or a vein. If these instructions are scrambled, the vessels fail to separate properly, leading to direct connections between arteries and veins. Even in these inherited cases, however, the disease does not always appear. The researchers noted that a person might carry the faulty gene but never develop a malformation, suggesting that a second, local event is often needed to trigger the problem.

In the majority of cases, where there is no family history, the malformations arise from a different kind of genetic error. These are not inherited from parents but occur spontaneously in the cells of the blood vessel wall itself. The researchers discovered that in these sporadic cases, the cells lining the vessels often carry a specific mutation in a gene called KRAS. This gene acts as a switch that controls cell growth. When it is stuck in the "on" position due to a mutation, it sends a constant signal for the cells to multiply and form new vessels. This creates a runaway growth of abnormal blood vessels. The researchers found that these mutations are present in a significant portion of sporadic brain malformations, with KRAS being the most common culprit (identified in a pooled estimate of 55% of cases), followed by a related gene called BRAF (identified in 7.5% of cases). Crucially, these mutations are not found in every cell of the body, but only in the cells of the malformation itself, making them difficult to detect without highly sensitive testing.

The review also highlighted that the genetic error is only part of the story. Once the abnormal vessels begin to form, they trigger a cycle of inflammation and tissue remodeling. The body sends immune cells to the area, releasing chemicals that break down the surrounding tissue and weaken the vessel walls further. This creates a self-sustaining loop where the abnormal vessels cause inflammation, and the inflammation makes the vessels more likely to rupture. The researchers also looked at other genetic factors that might influence how severe the condition becomes. They found that certain common variations in the human genome, such as those near the 9p21 region, do not cause the malformation on their own but may make the vessel walls more vulnerable to bleeding. Similarly, variations in genes that control inflammation, like IL6 and TNFα, appear to be linked to whether a patient experiences a hemorrhage.

To confirm that these genetic findings were real and not just coincidental, the researchers examined experimental studies where scientists created similar conditions in mice. In these models, scientists activated the KRAS gene specifically in the blood vessel cells, and the mice developed brain malformations that looked and behaved exactly like the human disease. When the researchers blocked the signaling pathway that KRAS uses, the abnormal growth stopped. This provided strong evidence that the genetic mutations found in human patients are indeed the direct cause of the disease. The experiments also showed that the AVM phenotype could be reversed in a specific KRAS-driven model if the genetic switch was turned off early enough, offering a glimmer of hope for future treatments.

Despite these significant discoveries, the researchers were careful to note the limits of current knowledge. While they have identified the primary genetic drivers, the tools to detect these mutations in living patients are not yet perfect. Because the mutations are present in only a small fraction of the cells within the malformation, standard tests often miss them. Furthermore, while the genetic causes are becoming clear, the link between a specific mutation and the risk of a future bleed remains uncertain. A patient with a KRAS mutation does not necessarily have a higher risk of bleeding than one without it, as the risk is also heavily influenced by the physical shape of the vessels and the pressure of the blood flow.

The review concludes that cerebral arteriovenous malformations are the result of a convergence between inherited weaknesses and random, local genetic errors. Both paths lead to the same destination: a failure of the blood vessels to mature and stabilize. The discovery of these molecular mechanisms shifts the perspective from viewing these malformations as unexplainable accidents to seeing them as biological events with a clear cause. This understanding opens the door to new ways of thinking about treatment. Instead of relying solely on surgery or radiation to remove the tangle, researchers are now exploring whether drugs that target these specific genetic pathways could stop the growth or even shrink the malformation. However, the authors emphasize that these targeted therapies are still in the experimental stage and have not yet been proven safe or effective for humans. For now, the primary value of this research lies in its ability to explain the "why" behind the disease, providing a solid foundation for the development of future, more precise medical interventions.