Dural Arteriovenous Fistula (DAVF) Formation

Definition
Dural arteriovenous fistulas (DAVFs) are acquired vascular malformations characterized by abnormal shunts between dural arteries and dural venous sinuses or cortical veins, located within the dura mater.

• Venous Hypertension: Often triggered by cerebral venous sinus thrombosis or stenosis, leading to retrograde venous pressure and hypoxia in the dura mater.
• Angiogenesis: Hypoxia induces upregulation of HIF-1α and VEGF, promoting neovascularization. Aberrant vessels may bypass normal capillary beds and form shunts.
• Inflammation: Local inflammation promotes endothelial proliferation, matrix remodeling, and vessel wall disruption, contributing to arteriovenous channel formation.
• Failure of Vascular Maturation: Absence of pericyte stabilization and immature vessel networks lead to persistent AV connections.

• Cerebral venous sinus thrombosis
• Cranial trauma or prior neurosurgery
• Chronic infections or inflammation
• Hypercoagulable states
• Hormonal influences (e.g., pregnancy, contraceptives – debated)

• Transverse-sigmoid sinus
• Cavernous sinus
• Superior sagittal sinus
• Tentorial or anterior fossa dura

Animal models (e.g., rat venous hypertension models) demonstrate increased angiogenesis but rarely true DAVF formation. They lack the structural and hemodynamic complexity of human DAVFs, limiting translational value.

Understanding DAVF formation aids in:

• Early identification of at-risk patients (e.g., after venous thrombosis)
• Exploring pharmacological inhibition of angiogenesis and inflammation
• Preventing DAVF development in prothrombotic or post-traumatic settings
• Informing endovascular and surgical management based on angioarchitecture

Iatrogenic complications such as pseudoaneurysms formation or dural arteriovenous fistulas (dAVFs) formation-has been identified in rare cases after the surgical intervention for revascularizations. We describe two cases. In first case, the patency of the anastomosis site was good and saccular type pseudoaneurysm formation was found at parietal branch of posterior middle meningeal artery (MMA) in transfemoral cerebral angiography (TFCA) performed on the twelfth day after surgery. We decided to treat pseudoaneurysm by endovascular embolization the next day, but the patient was shown unconsciousness and anisocoria during sleep at that day. Computed tomography showed massive subdural hemorrhage at the ipsilateral side, thus we performed decompressive craniectomy and hematoma evacuation. In second case, the patency of the anastomosis site was good and dAVF formation at right MMA was found in TFCA performed on the sixth day after surgery. They performed endovascular obliteration of the arteriovenous fistula under local anesthesia. Pseudoaneurysm formation or dAVF formation after revascularization surgery is an exceptional case. If patients have such complications, practioner should carefully screen the patients by implementing digital subtraction angiogram to identify anatomic features; as well as consider immediate treatment in any way, including embolization or other surgery ¹⁾.

In a Preclinical Experimental Study Zou et al. ²⁾ from the Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China, evaluated in the Journal of neurosurgery the antiangiogenic effect of 2-methoxyestradiol (2-ME) in a rat model of intracranial venous hypertension, used as a proxy to study dural arteriovenous fistula formation. Specifically, the authors aimed to determine whether 2-ME could reduce angiogenesis in the dura mater by modulating the HIF-1α and ID-1 pathways, which are implicated in hypoxia-induced neovascularization, and concluded that 2-ME could potentially serve as a therapeutic agent to modulate angiogenesis caused by intracranial venous hypertension — a process they consider central to DAVF development.

🚩 1. Flawed Model: DAVF Without DAVF

Despite the title and clinical framing, this study does not model dural arteriovenous fistulas (DAVFs).

No arteriovenous shunt is demonstrated.

No hemodynamic assessment is performed.

No imaging or functional endpoints validate that the model reflects DAVF pathophysiology.

👉 What the authors present is not a DAVF model, but a crude simulation of dural angiogenesis via venous outflow obstruction. Calling it a DAVF model is scientifically misleading.

🧬 2. Redundant Pathway Confirmation

Downregulation of HIF-1α and ID-1 in hypoxic tissues treated with 2-ME is entirely expected.

These markers are ubiquitously involved in hypoxia-induced angiogenesis.

There is no novelty in confirming their suppression by a known antiangiogenic drug.

The authors fail to explore alternative mechanisms or compare 2-ME to other compounds.

👉 This is confirmation science, not discovery.

📊 3. Overreliance on Surrogate Endpoints

The study relies entirely on:

Microvessel density (MVD)

Western blot and RT-PCR of proangiogenic markers

Histological staining

None of these endpoints translate meaningfully to clinical DAVF formation, rupture, or treatment. 👉 The antiangiogenic effect is localized, temporary, and lacks functional relevance to disease.

🧠 4. No Clinical Bridge

The authors suggest therapeutic potential of 2-ME for DAVFs, but:

There is no clinical data, not even a case report.

No discussion of 2-ME’s pharmacokinetics in CNS tissues, toxicity, or interaction with neurovascular structures.

No rationale is given for choosing 2-ME over other better-studied antiangiogenics.

👉 The leap from a rodent dura to human neurosurgical treatment is speculative and unjustified.

🔬 5. Lack of Rigor in Experimental Design

The control groups are poorly described.

There is no blinding, randomization, or power analysis.

The sample size (n = 72) sounds robust, but is split across multiple subgroups and timepoints, undermining statistical strength.

👉 This is methodological inflation without analytical depth.

📣 6. Misleading Framing and Title

The title implies an intervention for DAVF formation. In reality:

No DAVFs were formed.

No angiographic, surgical, or neuroimaging endpoints were measured.

The real subject is antiangiogenesis in the rat dura. Full stop.

👉 This is scientific misbranding to create false clinical impact.

📉 Final Assessment

This study is a laboratory exercise exaggerated into a clinical narrative. It offers:

No pathophysiological insight.

No clinical translation.

No novel mechanism.

It is a classic example of bench-to-nowhere science: technically competent but biologically and clinically irrelevant.

🔥 Verdict:

Rating: ★☆☆☆☆

Summary:

“A rat study in search of a disease.”

Elegant immunohistochemistry cannot rescue a flawed concept.