Ischemic stroke represents a global health challenge [1]. The critical role of cerebral perfusion status in early neurological deterioration and its impact on long-term outcomes is well-known [2]. A promising approach is to reinforce transdural angiogenesis, which involves the formation of new blood vessels across the dura mater [3,4]. This novel concept is supported by the results of a recent randomized controlled study aimed at enhancing cerebral perfusion in the ischemic penumbra [5].

Transdural angiogenesis offers a potential alternative to address the limitations of current acute treatment modalities, such as thrombolysis and endovascular clot retrieval [6,7]. This could be particularly beneficial for patients with cerebral perfusion impairment due to conditions, such as intracranial atherosclerotic stenosis or progressive moyamoya disease, particularly when conventional medical therapies are inadequate.

Furthermore, the implementation of invasive revascularization surgery raises concerns regarding associated adverse events [8]. The multiple burr hole (MBH) procedure, a relatively safe and indirect bypass strategy, has been cautiously employed as a standalone revascularization modality [9]. Despite its advantage at lowering the risk of perioperative complications [10], the MBH procedure may have the disadvantage that it does not always guarantee stable arteriogenesis via transdural detours [11,12]. Currently, there is limited research on this approach, particularly concerning moyamoya disease or proximal vessel occlusion with intracranial perfusion impairment [3-5,13,14].

Theoretically, combining the MBH procedure with angiogenic boosters holds promise for achieving safe and effective transdural arteriogenesis. Herein, we aimed to describe the reinforcement of transdural angiogenesis as a promising therapeutic approach, with the potential to revolutionize ischemic stroke management. This approach addresses the critical need for improved treatment options in patients with ischemic stroke and cerebral perfusion impairment.

The ischemic penumbra refers to the region of at-risk yet viable tissue surrounding the irreversibly damaged ischemic core region in cases of acute cerebral ischemia [15]. The primary goal of acute stroke treatment is to salvage the penumbral tissue and enhance brain function [16,17]. However, many patients with acute stroke and treatable penumbrae fail to receive treatment within the limited time window [18]. Cerebral hypoperfusion in the ischemic penumbra can exacerbate cerebral infarction, which is a devastating outcome in patients with acute ischemic lesions. Consequently, effective non-recanalization therapeutics with cerebral blood flow augmentation are required to address this clinical challenge.

In this context, revascularization surgery that induces tertiary collateral formation offers a novel therapeutic option for the cerebral ischemic penumbra. The terms “transdural collateral” or “tertiary collateral” are commonly used to describe the formation of new blood vessels or the maturation of pre-existing vessels in ischemic areas across the dura mater [19]. Figure 1 presents a schematic illustration of the ischemic cerebral penumbra and the classification of the different cerebral collateral networks used to prevent cellular death in the penumbral tissue. Angiogenesis and arteriogenesis are the two primary procedures involved in this process. Angiogenesis, which is primarily triggered by ischemia and hypoxia, is the physiological process in which new blood vessels originate from preexisting vessels [20]. In contrast, arteriogenesis refers to the maturation of preexisting arterioles into arteries, driven by shear stress on the endothelium generated by pressure gradients [21]. These processes require time to develop, and are particularly relevant in cases of chronic vascular occlusion. Tertiary collateral formation is commonly observed during the development of moyamoya vessels in patients with moyamoya disease and syndrome [22,23].

Therefore, understanding cerebral hypoperfusion and collateral strategies is critical for managing the ischemic penumbra, particularly among patients with cerebral perfusion impairment. Revascularization surgery has emerged as a promising intervention to address the multifaceted challenges of this condition and to potentially improve patient outcomes.

Transdural or tertiary collateral circulation can originate from various extracranial sources, including the branches of the external carotid artery (ECA) and cervical arteries [19,24]. Understanding the anatomy and dynamics of these collateral pathways is crucial for managing ischemic conditions in patients with acute stroke undergoing revascularization surgery or endovascular reperfusion therapy to salvage at-risk tissues in the ischemic penumbra [19,25].

Several extracranial sources may contribute to collateral circulation when blood vessel occlusion occurs (Figure 2). These sources may arise from branches of the ECA, or the ascending and deep cervical arteries. One notable example is the occlusion of the internal carotid artery (ICA) prior to the emergence of the ophthalmic artery. In patients with a complete and functional circle of Willis (CoW), retrograde flow through the circle can restore anterograde flow through the ophthalmic artery. However, inadequate collateral circulation through the CoW may necessitate alternative sources of blood flow, such as the branches of the ECA that can anastomose with the ophthalmic artery branches, ultimately reaching the terminal ICA [24].

Transdural angiogenesis, which involves the formation of novel blood vessels across the dura mater, has long been used in stroke therapy. Traditionally, bypass revascularization surgeries have focused on establishing anastomoses of the transdural collaterals, primarily using the superficial temporal artery (STA), a branch of the ECA located outside the skull, to the middle cerebral artery. This approach offers a perspective for enhancing cerebral perfusion in ischemic cortical regions. The middle meningeal artery (MMA), which is positioned inside the skull, was considered less significant for these collaterals. However, recent findings have indicated that successful transdural revascularization can also be achieved using branches within the skull (the intracalvarial MMA) or outside the skull (the extracalvarial STA or occipital artery) from the ECA [14]. This highlights the potential versatility of transdural angiogenesis in optimizing cerebral blood flow in ischemic areas, thereby expanding beyond previous surgical approaches.

Cerebral hemodynamic impairment and recurrent ischemic symptoms have traditionally guided treatment decisions in patients with moyamoya disease/syndrome [10,12,26-31]. Recently, one clinical study using an asymptomatic moyamoya registry reevaluated treatment indications for asymptomatic patients to clarify long-term prognosis and identify stroke risk factors [32]. The role of antiplatelet medication in patients with hemodynamically stable, asymptomatic, or mildly symptomatic moyamoya disease with cerebral hypoperfusion remains controversial, with ongoing debates and a paucity of randomized trials assessing the impact of conservative therapy [33].

Revascularization surgery has been established as the standard treatment to prevent recurrent stroke in patients with symptomatic moyamoya disease [26]. Recent evidence highlights that extracranial-intracranial bypass can notably reduce the risk of rebleeding in patients with hemorrhagic moyamoya disease [34]. The primary objectives of revascularization surgery include restoring the blood supply, stabilizing cerebrovascular hemodynamics, and regressing fragile moyamoya vessels to prevent bleeding, thereby enhancing secondary stroke prevention and improving neurological and neurocognitive outcomes.

In one recent clinical trial, the efficacy and safety of transdural revascularization procedures using MBHs [12,29,35]. with or without erythropoietin (EPO) pretreatment, were investigated in patients with acute symptomatic stroke [5]. These patients had grade 2 or higher perfusion impairments within 14 days of symptom onset, steno-occlusive findings on imaging, and no evidence of transdural collaterals on transfemoral cerebral angiography. Approximately 26% of patients (11/42) had moyamoya disease, while the rest had ischemic stroke with perfusion impairment. This study reported significant improvements in hemispheric perfusion parameters, while successful transdural revascularization was observed at the 6-month follow-up, particularly in patients who underwent the combined MBH procedure and EPO treatment (Figure 3A-C). Despite the vulnerability of patients with acute stroke to surgical complications, adverse events remain within acceptable limits, indicating the safety of combined therapy [5,12]. The MBH technique involves placing the patient in a supine position and administering local anesthesia. Subsequently, scalp incisions are made, and burr holes are drilled. Bone bleeding from the diploic veins can be managed using bone wax, while the dura is incised to facilitate collateral formation. The incision is then closed using sutures and staples. Furthermore, a preclinical study showed that mechanical barrier disruption, such as the burr hole procedure, successfully induces reverse arteriogenesis in healthy ECA in rat models [4,36]. These findings align with those of prior studies, indicating that MBH procedures combined with EPO can promote vasculogenesis, even in acute environments. In addition, in one animal model with impaired cerebral perfusion, combination therapy with MBH and EPO enhanced both the formation of new blood vessels (angiogenesis), and the maturation of existing vessels (arteriogenesis), in a reverse directional mode involving the transdural collaterals (Figure 3D-G).

Serological markers reveal how combining the MBH procedure with EPO enhances transdural revascularization in patients with acute stroke and perfusion impairment [3,5]. EPO primes arteriogenesis, while the MBH procedures facilitate vessel sprouting across the intracranial and extracranial boundaries. This process forms transdural collaterals that compensate for inadequate internal carotid flow. Enhanced extracranial conditions support arteriogenesis through shear stress and cytokines. Baseline biomarkers can also predict treatment efficacy [4]. Previous studies have indicated that increased MMP-9 levels correlate with successful revascularization [4].

In one clinical study involving patients with acute stroke and perfusion impairment treated with MBH and EPO, revascularization patterns were categorized as intracalvarial, extracalvarial, or balanced. Interestingly, whether the transdural collaterals originated inside or outside the skull did not influence the extent of revascularization. Follow-up ultrasonography revealed a significant decrease in ECA pulsatility when intracalvarial ECA collaterals were formed. These findings underscore the potential significance of intracalvarial ECA collateral revascularization strategies in patients with acute stroke [14]. Figure 4 presents the process of transdural revascularization via the wound healing of the dura mater post-MBH procedure. This schematic illustrates how the burr-hole technique facilitates blood vessel growth and repair across different meningeal layers (the dura mater, and potentially the pia mater), underscoring the role of surgical techniques in enhancing vascular healing and cerebral perfusion.

Owing to the crucial role of transdural angiogenesis in stroke treatment, current research has increasingly emphasized the strategies to promote angiogenesis and restore blood flow. Augmenting revascularization with angiogenic inducers, with or without the MBH procedure, offers the potential to enhance transdural angiogenesis in stroke patients with impaired cerebral blood flow, and is supported by clinical and animal studies [4,5]. Figure 5 outlines the potential signaling pathways for angiogenic agents that promote angiogenesis and improve cerebral perfusion.

MBH induces temporary wound injury and repair by mechanically disrupting the protective layers of the brain, and establishing a pathway between the intracranial and extracranial carotid systems [4]. However, MBH alone does not guarantee the stable formation of new vessels via transdural collaterals from the enriched extracranial environment [4]. As such, combining the MBH procedure with potential angiogenic boosters such as EPO is recommended for transdural revascularization in acute ischemic stroke with perfusion impairment. Prior studies have highlighted enhanced transdural angiogenesis and reverse arteriogenesis induced by the MBH procedure combined with EPO pretreatment [3-5,14]. The MBH procedure disrupts the dura mater, thereby facilitating a direct connection between the extracranial and intracranial circulations, potentially aiding vessel formation in an enriched extracranial environment. Transcranial or transdural vascular anastomosis, along with vascular networks in the galea and periosteum during the healing of bony defects, indicates a regenerative role for the periosteum in vessel formation [4].

In the experimental model, combination therapy progressed through distinct phases, starting with intracranial hypoxia following bilateral ICA ligation [4]. MBH disrupts the dura mater barrier between the intracranial and extracranial environments, thereby initiating retrograde vessel sprouting from the extracranial endothelium. Newly formed transcranial vascular connections occur alongside the normal wound healing stages of inflammation, proliferation, and angiopoietic remodeling. EPO pretreatment enhances arteriogenesis, facilitating mature vessel formation with upregulated expression of key genes, such as TGF-β and MMP-2. Together, the MBH procedure for angiogenic pathways and EPO administration as an arteriogenic booster synergizes to promote “reverse arteriogenesis” in cases of intracranial perfusion insufficiency [4].

Figure 6 presents a possible mechanism of transdural angiogenesis boosted by combined MBH and EPO treatment. Step 1 (baseline): Despite intracranial hypoxia from bilateral ICA ligation, there is a favorable extracranial milieu, with a mechanical barrier separating the intracranial and extracranial spaces, thereby initiating regional revascularization (Figure 6). Step 2 (acute): MBH breaks this barrier, allowing extracranial wound healing to stimulate vessel sprouting from the quiescent extracranial endothelium, with circulating angiogenic cytokines forming a chemotactic gradient. Step 3 (subacute): Successful transdural collaterals restored brain perfusion, with enhanced vessel stability observed in the combined MBH and EPO groups compared to the MBH procedure alone. Step 4 (chronic): EPO pretreatment promotes arteriogenesis, fostering mature vessel development via gene modulation, favoring anti-inflammatory cytokines, angiogenesis, and vessel maturation [4].

Modulation of the cerebral milieu to promote reverse arteriogenesis through pretreatment with MBH and EPO is a promising novel therapeutic strategy for acute ischemic stroke management. This combination therapy addresses both the extracranial and intracranial aspects of vessel formation and maturation, thereby potentially improving the outcomes in patients with ischemic stroke, progressive moyamoya, and severe cerebral perfusion impairment. Further research and clinical investigations are required to fully explore the clinical applicability of this innovative approach.