Reinforcement of Transdural Angiogenesis: A Novel Approach to Treating Ischemic Stroke With Cerebral Perfusion Impairment
Article information
Abstract
Cerebral hypoperfusion plays a critical role in early neurological deterioration and long-term outcomes in patients with acute ischemic stroke, which remains a major global health challenge. This review explored transdural angiogenesis as a promising therapeutic strategy to restore cerebral perfusion in patients with ischemic stroke. The multiple burr hole procedure has been preliminarily used as an indirect revascularization method to induce transdural arteriogenesis. Theoretically, its efficacy could be enhanced by combining it with angiogenic boosters, such as erythropoietin. Recent clinical and preclinical studies have revealed that this combination therapy promotes angiogenesis and arteriogenesis, leading to successful revascularization across the dura mater and improved cerebral blood flow. This strategy may be particularly beneficial for high-risk patients with recurrent ischemic events, such as those with moyamoya disease or intracranial arterial occlusion, representing an effective strategy when conventional medical treatments are insufficient. This review highlights the potential of transdural angiogenesis enhancement as a novel intervention for ischemic stroke, offering an alternative to thrombolysis or endovascular treatment, particularly in acute stroke patients with impaired cerebral perfusion. This approach has the potential to bridge the treatment gap for patients outside the therapeutic window for acute stroke interventions. Although further research is required to refine this technique and validate its efficacy in broader clinical settings, early results have revealed promising outcomes at reducing stroke-related complications and improving patient prognosis. This review indicates that this novel strategy may offer hope for managing ischemic stroke and related conditions associated with significant cerebral hypoperfusion.
Introduction
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.
Cerebral ischemic penumbra and cerebral collateral circulations
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].
A schematic representation of the ischemic penumbra in the brain and classification of the cerebral collateral circulation [80]. (A) The affected brain injury area (core: black area; penumbra: grey area) resulting from ICA occlusion. (B) Protective collateral detours: the primary collaterals comprise the arterial segments within the circle of Willis; the secondary collaterals include the anterior and middle cerebral arteries; and the tertiary collaterals comprise the superficial temporal artery extracranially and middle cerebral arteries intracranially. ICA, internal carotid artery; ECA, external carotid artery; CCA, common carotid artery.
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.
Anatomy and significance of transdural angiogenesis in collateral circulation
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].
Potential transdural revascularization patterns from the ECA following cranial MBH procedures in cases of cerebral hypoperfusion, including: (A) intracalvarial ECA patterns, (B) extracalvarial ECA patterns, and (C) balanced or mixed patterns. MBH, multiple burr hole; ICA, internal carotid artery; ECA, external carotid artery; CCA, common carotid artery; MMA, middle meningeal artery; MA, maxillary artery; STA, superficial temporal artery. Adapted from Lee et al. Stroke Vasc Neurol 2024:svn-2023-002831 [14], under the terms of the Creative Commons Attribution (CC BY 4.0) License.
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.
Transdural revascularization in moyamoya disease and acute ischemic stroke
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).
A representative case of transdural angiogenesis treated with combination therapy involving the MBH procedure and EPO in a patient with initial perfusion impairment. (A) Representative image of combination therapy in the left hemisphere of a 74-year-old female. (B) Angiography at baseline and 6 months following combination therapy. (C) Computed tomography perfusion scans at baseline and 6 months after combination therapy. Adapted from Hong et al. Stroke 2022;53:2739-2748 [5], under the terms of the Creative Commons Attribution (CC BY 4.0) License. (D) Representative image of the vessels stained with rat endothelial cell antigen 1 (RECA-1) at 1 month, with (ipsilateral hemisphere) or without (contralateral hemisphere) the MBH procedure (scale bar=400 μm). (E) Angiogenesis and arteriogenesis by double-staining of RECA-1 and alpha smooth muscle actin (α-SMA) in the MBH procedure, or combination with EPO at 1 (upper panel) and 3 (lower panel) months (scale bar=100 μm). (F and G) Quantification of the vessel area (%) by RECA-1 and vessel maturation (%) by double-staining of RECA-1 and α-SMA in the ipsilateral hemisphere. *P<0.05; **P<0.01; ***P<0.001; †P<0.05. Adapted from Park et al. Neurobiol Dis 2019;132:104538 [4], under the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) License. MBH, multiple burr hole; EPO, erythropoietin; ICA, internal carotid artery; CBF, cerebral blood flow; CBV, cerebral blood volume; TTP, time to peak; MTT, mean transit time.
Potential factors influencing successful transdural angiogenesis: local wound healing of the dura mater
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.
Transdural revascularization facilitation through wound healing of the dura mater [4, 14]. (A) Schematic illustration of: (a) the burr hole extending through the inside skull level, (b) the burr hole extending through the dura mater level, and (c) the burr hole extending through the pia mater level. (B) A case example illustrating combination therapy, and emphasizing the crucial role of the dura mater breakdown in successful transdural revascularization. In the lateral view of the left common carotid angiogram: (a) No revascularization could be observed when the MBH was made without opening the dura mater, (b) Revascularization was observed when the dura mater was disrupted, (c) Revascularization was also noted when the MBH extended from the dura mater to the pia mater. (C) Three months post-burr hole procedure, postmortem cerebral angiography was performed using a transcardial injection of black gelatin solution. After lifting the rat’s skull, a visible transdural anastomosis was observed. The in vivo image showing the critical role of the burr-hole procedures around the skull in achieving successful transdural revascularization (scale bar=1 mm). Adapted from Park et al. Neurobiol Dis 2019;132:104538 [4], under the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) License. MBH, multiple burr hole.
Potential biological boosters of augmented revascularization
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.
The signaling pathway for treatment of angiogenic boosting. Erythropoietin, a crucial cytokine for hematopoiesis, significantly boost angiogenesis by elevating the expression of nitric oxide (NO) and vascular endothelial growth factor (VEGF) and its receptor, which are critical for new blood vessel development. Similarly, statins, which are commonly used to reduce lipid levels, also promote angiogenesis in ischemic conditions by enhancing neurogenesis and upregulating VEGF. Phosphodiesterase inhibitors, such as cilostazol and sildenafil, improve cerebral endothelial function and angiogenesis by activating endothelial NO synthase (eNOS), which increases NO levels. This overall enhancement of angiogenesis crucially upregulates endothelial cell viability and function, thereby aiding in the recovery of cerebral blood flow (CBF).
Erythropoietin
EPO is a key cytokine in hematopoiesis that regulates the formation of red blood cells [37,38]. The physiological function of EPO regulates various physiological processes including angiogenesis, anti-apoptosis, neuroprotection, and neurogenesis [39-42]. Clinical studies have revealed that EPO is a potential therapeutic agent for treating a variety of diseases, particularly ischemic stroke [5,43,44]. Several preclinical studies have indicated that EPO treatment induces neuroprotection by enhancing angiogenesis and neurogenesis [4,43,45-47]. EPO treatment recovers cerebral blood flow in the penumbral region and improves neurological outcomes in animal models of cerebral ischemia [45,48-50]. EPO treatment has been found to elevate the expression of vascular endothelial growth factor (VEGF) [4,46,50,51] and VEGF receptor-2 [50]. Subsequently, it increases the expression of endothelial nitric oxide synthase (eNOS), ultimately promoting angiogenesis during cerebral ischemia [52,53].
Statins
Statins, also known as hydroxymethylglutaryl coenzyme A reductase inhibitors, are commonly prescribed for lipid reduction [54,55]. Furthermore, statins have been found to promote collateral development in ischemic vascular disease [56,57], making them a widely recommended medication for the secondary prevention of ischemic stroke [54,58]. However, there is currently a lack of clinical and preclinical studies on angiogenesis resulting from the therapeutic combination of the burr hole procedure and statin treatment. Prior research in animal models has demonstrated that statin treatment alone protects the ischemic brain by enhancing angiogenesis and neurogenesis [59-62]. Statins induce angiogenesis in the ischemic brain tissue by upregulating the expression of VEGF [59,60]. Statins also stimulate nitric oxide (NO)-mediated angiogenesis by activating the phosphatidylinositol 3-kinase–protein kinase B pathway [63-65].
Phosphodiesterase inhibitors
Endothelial dysfunction serves as an initial indication of compromised angiogenesis in ischemic stroke [6,66]. The use of phosphodiesterase inhibitors, such as cilostazol and sildenafil, has been shown to improve cerebral endothelial function and blood flow in patients with ischemic stroke [13,67-69]. Additionally, cilostazol treatment enhances angiogenesis by improving endothelial function in various experimental models of ischemia [70-72]. This mechanism involves eNOS activation, which is essential for enhancing angiogenesis and endothelial function [73-75]. Sildenafil has similar effects at increasing angiogenesis and endothelial function in various preclinical ischemic models [76-78]. In one experiment involving sildenafil treatment, eNOS was found to also play a central role in promoting angiogenesis and endothelial function [77,79].
MBH procedure and angiogenic boosting: a reinforcement strategy for transdural angiogenesis
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].
Plausible mechanism of the transdural angiogenesis boosted by combining the MBH procedure and EPO treatment. The transdural angiogenesis process facilitated by the MBH procedure and EPO treatment involves disrupting the barrier between the intracranial and extracranial regions, which promotes vessel sprouting and the activity of angiogenic cytokines. As treatment progresses, EPO significantly enhances arteriogenesis by upregulating genes linked to related anti-inflammatory and maturation processes. This leads to improved brain perfusion and greater stability of new vessels, showing enhanced outcomes compared to treatments with the MBH procedure alone. MBH, multiple burr hole; EPO, erythropoietin; ICA, internal carotid artery; ECA, external carotid artery; BBB, blood–brain barrier; VEGF, vascular endothelial growth factor; VEGFR-2, VEGF receptor-2; PDGF-β, platelet-derived growth factor beta. Adapted from Park et al. Neurobiol Dis 2019;132:104538 [4], under the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) License.
Conclusion
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.
Notes
Funding statement
This work was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant numbers: HR21C1003 and HR22C1734). The funding sources played no role in this study.
Conflicts of interest
The authors have no financial conflicts of interest.
Author contribution
Conceptualization: JMH, HSS. Study design: JMH. Methodology: JMH, HSS. Data collection: JMH, HSS. Investigation: JMH, HSS. Statistical analysis: JMH, HSS. Writing—original draft: JMH, HSS. Writing—review & editing: JMH, HSS. Funding acquisition: JMH. Approval of final manuscript: all authors.