J Stroke.  2025 Jan;27(1):30-40. 10.5853/jos.2024.02810.

Reinforcement of Transdural Angiogenesis: A Novel Approach to Treating Ischemic Stroke With Cerebral Perfusion Impairment

• Hong JM
• Shin HS

• KMID: 2564260
• DOI: http://doi.org/10.5853/jos.2024.02810

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.

Keyword

Ischemic stroke; Moyamoya disease; Angiogenesis; Erythropoietin; Dura mater

Figure

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  Figure 1. 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.

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  Figure 2. 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.

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  Figure 3. 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.

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  Figure 4. 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.

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  Figure 5. 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).

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  Figure 6. 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.

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