Brain arteriovenous malformations (AVMs) result from a combination of genetic mutations and disrupted blood vessel development, most often beginning before birth. These tangles of abnormal blood vessels affect roughly 1.3 per 100,000 people, and while they were long considered purely congenital defects, newer evidence shows they can also form or change throughout life. The causes are complex, involving multiple biological pathways rather than a single trigger.
How Normal Blood Vessels Differ From an AVM
In a healthy brain, arteries carry oxygen-rich blood and gradually branch into smaller and smaller vessels until they reach capillaries. These tiny capillaries slow blood flow, deliver oxygen through their thin walls to surrounding brain tissue, and then funnel blood into veins for the return trip to the heart. The capillary bed acts as a critical buffer between the high-pressure arterial system and the low-pressure venous system.
In a brain AVM, that capillary network is missing entirely. Arteries connect directly to veins through a tangled cluster of vessels called a nidus. Blood rushes from arteries to veins without slowing down, which means nearby brain tissue gets shortchanged on oxygen. It also puts extreme pressure on vessel walls that were never built to handle it, causing them to stretch thin and weaken over time. This is why AVMs carry a 2% to 4% annual risk of bleeding.
Somatic Mutations in the MAPK Pathway
The most significant genetic discovery in AVM research involves mutations in a cell-signaling chain called the MAPK pathway, which controls how blood vessel cells grow, divide, and organize. Researchers performing whole-exome sequencing on AVM tissue have found that the KRAS gene is the most commonly mutated. Two specific KRAS mutations, known as G12V and G12D, appear in a large share of sporadic (non-inherited) brain AVMs. In one study published in the Journal of Neurosurgery, the G12D mutation was present in nearly 32% of AVM samples, while G12V appeared in about 14.5%.
These mutations are somatic, meaning they occur only in the cells of the malformation itself, not throughout the body. When researchers compared DNA from AVM tissue to blood DNA from the same patients, the mutations appeared exclusively in the lesion. This pattern, called somatic mosaicism, explains why brain AVMs typically occur as isolated, one-off lesions rather than running in families.
Importantly, a single KRAS mutation may not be enough on its own. Researchers identified 24 candidate mutations across 11 different genes in the MAPK pathway, and some patients carried mutations in multiple genes simultaneously. This “multiple hit” model suggests that AVM formation requires several genetic errors stacking up in the same signaling pathway within the same cluster of cells.
The Role of Blood Vessel Growth Signals
A protein that stimulates new blood vessel growth, called vascular endothelial growth factor (VEGF), plays a key role in AVM development and progression. VEGF levels are significantly elevated in human AVM tissue compared to normal brain vasculature. In animal studies, mice that carried mutations linked to AVMs tolerated those mutations well under normal conditions. But when researchers added extra VEGF, or triggered new blood vessel growth through a wound, AVMs formed rapidly. On the flip side, blocking VEGF signaling in those same experimental models prevented AVMs from forming at all.
This finding helps explain why AVMs can remain stable for years and then change. Anything that ramps up VEGF production locally, including inflammation, injury, or hormonal shifts, could potentially destabilize an existing malformation or encourage a new one to develop.
Hereditary Hemorrhagic Telangiectasia
While most brain AVMs are sporadic, about 10% to 20% of people with a genetic condition called hereditary hemorrhagic telangiectasia (HHT) develop some type of brain vascular malformation. HHT is caused by inherited mutations in genes that regulate a signaling system involved in blood vessel stability. Over 80% to 90% of people with confirmed HHT carry a mutation in one of two genes: ENG or ACVRL1. Both genes encode receptors that help blood vessels maintain their structure and respond to growth signals appropriately.
The two gene variants produce slightly different patterns of disease. People with ENG mutations (classified as HHT1) are more likely to develop brain AVMs and lung vascular malformations. Those with ACVRL1 mutations (HHT2) tend to develop liver vascular malformations instead. In both cases, the underlying problem is the same: with only one functional copy of the gene, blood vessel cells don’t receive strong enough stabilization signals. This leaves them vulnerable to forming abnormal connections, particularly when other triggers like inflammation or injury are present.
Developmental Origins Before Birth
Most brain AVMs trace their beginnings to fetal development, when blood vessels are first forming and organizing in the brain. During this process, cells must correctly identify themselves as arterial or venous and recruit supporting cells (called pericytes and mural cells) that wrap around vessels to strengthen them. AVMs arise when this specification process goes wrong. Instead of building a proper capillary network between arteries and veins, the developing vessels form direct, chaotic connections.
The failure isn’t a complete halt in development but rather a breakdown in vascular stabilization and remodeling. The vessels form, but they never mature properly. They lack the structural support that normal capillaries have, resulting in fragile, disorganized tangles. Three signaling systems are consistently disrupted in this process: the RAS/MAPK pathway (controlling cell growth), the NOTCH pathway (controlling arterial versus venous identity), and the TGF-β pathway (controlling vessel stability). Interactions between blood vessel cells and surrounding brain cells like astrocytes are also impaired, further weakening the neurovascular unit.
AVMs Can Also Form After Birth
The traditional view that all brain AVMs are present from birth has been challenged by documented cases of de novo formation, where AVMs developed in brain tissue previously confirmed to be normal on MRI. A literature review identified several such cases, including some in patients with no prior vascular abnormalities at all. AVMs have also been shown to grow, shrink, and remodel over time, reinforcing the idea that they are dynamic rather than static.
The triggers for post-birth AVM formation appear to include mechanical injury, inflammation, blood clots, reduced oxygen supply, and hormonal changes. Any of these could theoretically push vulnerable vessel cells past a tipping point, particularly if those cells already carry low-level somatic mutations that hadn’t yet caused problems. The rarity of confirmed de novo cases suggests this sequence of events is uncommon, but it does happen. Notably, AVMs are diagnosed far more often in adults than in children, which is difficult to explain if every AVM were truly present from birth.
What Increases the Risk of Bleeding
Not all brain AVMs bleed, and the risk varies depending on the malformation’s characteristics. The overall annual hemorrhage rate for a previously unruptured AVM is about 1.9%. But if an AVM has already bled once, the annual risk of rebleeding jumps dramatically to roughly 7.5%, making prior hemorrhage the single strongest predictor. Two structural features also raise the risk: having only a single draining vein (which increases pressure within the nidus because blood has fewer escape routes) and a diffuse, spread-out shape rather than a compact one.
Seizures are the other common way brain AVMs reveal themselves, occurring as the initial symptom in about 24% to 40% of cases. In one large study, 29% of patients with brain AVMs first came to medical attention because of a seizure. Many AVMs, however, are discovered incidentally during brain imaging done for unrelated reasons and may never cause symptoms at all.