Dolichoectasia of the ophthalmic artery: a case report on the treatment strategy in endovascular therapy and literature review.

BACKGROUND: Dolichoectasia is a rare arterial condition characterized by the dilatation, tortuosity, and elongation of cerebral blood vessels. The vertebrobasilar artery and internal carotid artery are the common sites of dolichoectasia. However, dolichoectasia of the branch arteries, such as the ophthalmic artery (OA), is extremely rare. To the best of our knowledge, this is the first case of ophthalmic dolichoectasia that was successfully treated with endovascular internal coil trapping. CASE PRESENTATION: A 54-year-old female patient presented with transient left ophthalmalgia and visual disturbance. Magnetic resonance imaging revealed a dilated and elongated left OA compressing the optic nerve at the entrance of the optic canal. However, a previous image that was taken 17 years back revealed that the OA was normal, which suggested the change in dolichoectasia was acquired. Cerebral angiography showed that the dilated and tortuous OA was running from the ophthalmic segment of the left internal carotid artery into the orbit. The symptoms could have been attributed to the direct compression of the dolichoectatic OA in the optic canal. A sufficient anastomosis between the central retinal artery and the middle meningeal artery was identified on external carotid angiography with balloon occlusion of the internal carotid artery. Endovascular treatment with internal trapping of the OA was performed due to ophthalmic symptom progression. Internal coil trapping of the OA was performed at the short segment between the OA bifurcation and the entrance of the optic canal. As expected, the central retinal artery was supplied via the middle meningeal artery after the treatment. The transient visual disturbance was immediately resolved. Ophthalmalgia worsened temporarily after the treatment. However, it completely resolved after several days of oral corticosteroid therapy. Postoperative angiography showed that the origin of the OA was occluded and that the OA in the optic canal was shrunk. The flow of the central retinal arteries via the middle meningeal artery was preserved. CONCLUSIONS: OA dolichoectasia is rare, and its pathogenesis and long-term visual prognosis are still unknown. However, endovascular therapy can improve symptom by releasing the pressure site in the optic canal.

Vitamin D deficiency promotes intracranial aneurysm rupture.

Intracranial aneurysm rupture causes severe disability and high mortality. Epidemiological studies show a strong association between decreased vitamin D levels and an increase in aneurysm rupture. However, the causality and mechanism remain largely unknown. In this study, we tested whether vitamin D deficiency promotes aneurysm rupture and examined the underlying mechanism for the protective role of vitamin D against the development of aneurysm rupture utilizing a mouse model of intracranial aneurysm. Mice consuming a vitamin D-deficient diet had a higher rupture rate than mice with a regular diet. Vitamin D deficiency increased proinflammatory cytokines in the cerebral arteries. Concurrently, vitamin D receptor knockout mice had a higher rupture rate than the corresponding wild-type littermates. The vitamin D receptors on endothelial and vascular smooth muscle cells, but not on hematopoietic cells, mediated the effect of aneurysm rupture. Our results establish that vitamin D protects against the development of aneurysmal rupture through the vitamin D receptors on vascular endothelial and smooth muscle cells. Vitamin D supplementation may be a viable pharmacologic therapy for preventing aneurysm rupture.

Dietary Iron Restriction Protects against Aneurysm Rupture in a Mouse Model of Intracranial Aneurysm.

INTRODUCTION: Iron accumulation in vessel walls induces oxidative stress and inflammation, which can cause cerebrovascular damage, vascular wall degeneration, and intracranial aneurysmal formation, growth, and rupture. Subarachnoid hemorrhage from intracranial aneurysm rupture results in significant morbidity and mortality. This study used a mouse model of intracranial aneurysm to evaluate the effect of dietary iron restriction on aneurysm formation and rupture. METHODS: Intracranial aneurysms were induced using deoxycorticosterone acetate-salt-induced hypertension and a single injection of elastase into the cerebrospinal fluid of the basal cistern. Mice were fed an iron-restricted diet (n = 23) or a normal diet (n = 25). Aneurysm rupture was detected by neurological symptoms, while the presence of intracranial aneurysm with subarachnoid hemorrhage was confirmed by post-mortem examination. RESULTS: The aneurysmal rupture rate was significantly lower in iron-restricted diet mice (37%) compared with normal diet mice (76%; p < 0.05). Serum oxidative stress, iron accumulation, macrophage infiltration, and 8-hydroxy-2'-deoxyguanosine in the vascular wall were lower in iron-restricted diet mice (p < 0.01). The areas of iron positivity were similar to the areas of CD68 positivity and 8-hydroxy-2'-deoxyguanosine in both normal diet and iron-restricted diet mouse aneurysms. CONCLUSIONS: These findings suggest that iron is involved in intracranial aneurysm rupture via vascular inflammation and oxidative stress. Dietary iron restriction may have a promising role in preventing intracranial aneurysm rupture.

Improving the Reachability of Contact Aspiration for Acute Ischemic Stroke Using a New Delivery Assist Catheter.

OBJECTIVE: This study aimed to improve the reachability of large lumen catheter for contact aspiration during acute ischemic stroke by a new delivery assist catheter. METHODS: This study included 58 patients with large-vessel stroke treated using endovascular procedures at our institution and affiliated hospitals between July 2021 and January 2023. Contact aspiration, especially contact aspiration using nonpenetrating of thrombus (CANP) technique, was adopted as first-line thrombectomy for localized internal carotid artery, middle cerebral artery proximal (M1 segment), and basilar artery without tandem occlusion in acute stroke. The new delivery assist catheter (AXS Offset catheter, Stryker, Fremont, CA, USA) was standardized after its release. Results of this improved contact aspiration technique using the new delivery assist catheter, including reachability, procedure time, and first-pass effect, were compared with conventional catheters. RESULTS: Of the 58 patients, 43 underwent only thrombectomy for acute embolic stroke. CANP technique was attempted on 25 patients (25/43, 58.1%). Of these, a normal inner catheter (inner diameter: 0.021 or 0.027 inches) and the new delivery assist catheter were used on 10 (10/25, 40%) and 15 (15/25, 60%) patients, respectively. An aspiration catheter reached the thrombus for 5 patients (5/10, 50%) and 14 patients (14/15 93.3%) in the normal and new delivery assist catheter groups, respectively (P = 0.023). There was no significant difference in the results of contact aspiration due to the delivery catheter. CONCLUSIONS: The new delivery assist catheter improved the reachability of the aspiration catheter to the thrombus and is an effective device for performing CANP technique.

De novo dural arteriovenous fistula after mechanical thrombectomy for cerebral venous thrombosis: A case report.

Background: Although the relationship between dural arteriovenous fistula (dAVF) and cerebral venous thrombosis (CVT) has been reported, the etiology has not been clarified. Here, we report a case of de novo dAVF after mechanical thrombectomy for CVT and discuss the underlying mechanism. Case Description: A 61-year-old woman presented with a gradually worsening headache and was diagnosed with severe CVT. Mechanical thrombectomy was performed for the CVT because of progressive neurological deterioration despite anticoagulation therapy. Two years after the initial treatment, angiography revealed a de novo dAVF with a direct shunt of the left convexity cortical vein. Transarterial embolization with Onyx was performed and the shunt was completely obliterated. Conclusion: In this report, we describe a case of de novo dAVF with CVT that was treated with mechanical thrombectomy. Even if CVT improves with mechanical thrombectomy, we must be aware of the occurrence of de novo dAVF.

Occurrence of De Novo Dural Arteriovenous Fistula after Transvenous Embolization of Dural Arteriovenous Fistula : Case Reports of Two Patients.

Development of de novo dural arteriovenous fistula (DAVF) at a different site after resolution of an initial DAVF, is rare. Here we report two cases, which we encountered in our hospital. A 68-year-old woman presented with pulsatile tinnitus on the left side. Cerebral angiography demonstrated a left anterior condylar confluence (ACC) DVAF and she underwent transvenous embolization. Four years after this treatment, she presented with tinnitus on the left side, and cerebral angiography revealed a right DAVF around the sinus of the lesser sphenoid wing. Another 69-year-old woman presented with left-sided orbital bruits, chemosis, and conjunctival hyperemia. Cerebral angiography showed left cavernous sinus (CS) DAVF, for which she underwent transvenous embolization for CS DAVF. One year later, she developed a left ACC and transverse-sigmoid sinus (TSS) DAVF.

Roles of Phytoestrogen in the Pathophysiology of Intracranial Aneurysm.

Background and Purpose: The incidences of intracranial aneurysm and aneurysmal subarachnoid hemorrhage are high in postmenopausal women. Although population-based studies suggest that hormone replacement therapy is beneficial for postmenopausal women with intracranial aneurysms, estrogen replacement may no longer be recommended for the prevention of chronic diseases given its association with adverse outcomes, such as cancer and ischemic stroke. The isoflavone daidzein and its intestinal metabolite equol are bioactive phytoestrogens and potent agonists of estrogen receptors. Given their estrogenic properties, we investigated whether the isoflavones daidzein and equol are protective against the formation and rupture of intracranial aneurysms in a mouse model of the postmenopausal state. Methods: We induced intracranial aneurysms in ovariectomized adult female mice using a combination of induced systemic hypertension and a single injection of elastase into the cerebrospinal fluid. We fed the mice with an isoflavone-free diet with/without daidzein supplementation, or in a combination of intraperitoneal equol, or oral vancomycin treatment. We also used estrogen receptor beta knockout mice. Results: Both dietary daidzein and supplementation with its metabolite, equol, were protective against aneurysm formation in ovariectomized mice. The protective effects of daidzein and equol required estrogen receptor-ß. The disruption of the intestinal microbial conversion of daidzein to equol abolished daidzein's protective effect against aneurysm formation. Mice treated with equol had lower inflammatory cytokines in the cerebral arteries, suggesting that phytoestrogens modulate inflammatory processes important to intracranial aneurysm pathogenesis. Conclusions: Our study establishes that both dietary daidzein and its metabolite, equol, protect against aneurysm formation in ovariectomized female mice through the activation of estrogen receptor-ß and subsequent suppression of inflammation. Dietary daidzein's protective effect required the intestinal conversion to equol. Our results indicate the potential therapeutic value of dietary daidzein and its metabolite, equol, for the prevention of the formation of intracranial aneurysms and related subarachnoid hemorrhage.

Neutrophil Extracellular Traps Promote the Development of Intracranial Aneurysm Rupture.

[Figure: see text].

Transient Global Amnesia Following Coil Embolization for a Basilar-tip Aneurysm: Case Reports of Two Patients.

Transient global amnesia (TGA) can be caused by medications, ischemia, metabolic abnormalities, and seizures. We describe two cases of TGA following coil embolization for a basilar-tip aneurysm. A 73-year-old woman developed transient acute anterograde amnesia after coil embolization for a basilar-tip aneurysm. Diffusion-weighted imaging (DWI) revealed an ischemic lesion in the anterior nucleus of the thalamus. A 67-year-old woman developed transient acute amnesia after a stent-assisted coil embolization of a basilar-tip aneurysm. A DWI showed ischemic lesions in the anterior nucleus of the thalamus. Any ischemic changes to areas of the anterior nucleus that are fed by the thalamoperforating and premammillary arteries should be considered in a differential diagnosis for TGA in patients who have undergone coil embolization for a posterior circulation cerebral aneurysm.

Cisplatin-related Cerebral Infarction in Carcinoma of the External Auditory Canal.

BACKGROUND: Despite the known association between cisplatin and vascular toxicity, the mechanism of cisplatin-associated cerebral infarction, a relatively rare complication, remains unclear. We describe an investigation of potential biomarkers that could facilitate the early detection of this complication in a relevant case. CASE DESCRIPTION: A 59-year-old male diagnosed with stage III carcinoma of the external auditory canal underwent cisplatin chemotherapy. Seven days after the last dose, he presented with a disturbance of consciousness due to basilar artery occlusion, which was associated with chemotherapy administration. The patient recovered consciousness after thrombectomy. Interestingly, an increase in serum von Willebrand factor (vWf) activity was observed. The vWf activity level gradually normalized 5 months after cisplatin administration. CONCLUSIONS: Endothelial injuries could be responsible for cisplatin-associated cerebral infarction. Moreover, a cisplatin-induced cerebral infarction increase in serum vWf activity, which indicates endothelial injury, suggests that this molecule might be a useful biomarker for predicting cisplatin-associated cerebral infarction.

Sex and Genetic Background Effects on the Outcome of Experimental Intracranial Aneurysms.

BACKGROUND AND PURPOSE: Intracranial aneurysm formation and rupture risk are, in part, determined by genetic factors and sex. To examine their role, we compared 3 mouse strains commonly used in cerebrovascular studies in a model of intracranial aneurysm formation and rupture. METHODS: Intracranial aneurysms were induced in male CD1 (Crl:CD1[ICR]), male and female C57 (C57BL/6NCrl), and male 129Sv (129S2/SvPasCrl or 129S1/SvImJ) mice by stereotaxic injection of elastase at the skull base, combined with systemic deoxycorticosterone acetate-salt hypertension. Neurological deficits and mortality were recorded. Aneurysms and subarachnoid hemorrhage grades were quantified postmortem, either after spontaneous mortality or at 7 to 21 days if the animals survived. In separate cohorts, we examined proinflammatory mediators by quantitative reverse transcriptase-polymerase chain reaction, arterial blood pressure via the femoral artery, and the circle of Willis by intravascular latex casting. RESULTS: We found striking differences in aneurysm formation, rupture, and postrupture survival rates among the groups. 129Sv mice showed the highest rates of aneurysm rupture (80%), followed by C57 female (36%), C57 male (27%), and CD1 (21%). The risk of aneurysm rupture and the presence of unruptured aneurysms significantly differed among all 3 strains, as well as between male and female C57. The same hierarchy was observed upon Kaplan-Meier analysis of both overall survival and deficit-free survival. Subarachnoid hemorrhage grades were also more severe in 129Sv. CD1 mice showed the highest resistance to aneurysm rupture and the mildest outcomes. Higher mean blood pressures and the major phenotypic difference in the circle of Willis anatomy in 129Sv provided an explanation for the higher incidence of and more severe aneurysm ruptures. TNFα (tumor necrosis factor-alpha), IL-1ß (interleukin-1-beta), and CCL2 (chemokine C-C motif ligand 2) expressions did not differ among the groups. CONCLUSIONS: The outcome of elastase-induced intracranial aneurysm formation and rupture in mice depends on genetic background and shows sexual dimorphism.

TLR4 (Toll-Like Receptor 4) Mediates the Development of Intracranial Aneurysm Rupture.

Inflammation is emerging as a critical factor in the pathophysiology of intracranial aneurysm. TLR4 (toll-like receptor 4) contributes not only to the innate immune responses but also to the inflammatory processes associated with vascular disease. Therefore, we examined the contribution of the TLR4 pathway to the development of the rupture of intracranial aneurysm. We used a mouse model of intracranial aneurysm. TLR4 inhibition significantly reduced the development of aneurysmal rupture. In addition, the rupture rate and levels of proinflammatory cytokines were lower in TLR4 knockout mice than the control littermates. Macrophage/monocyte-specific TLR4 knockout mice had a lower rupture rate than the control littermate mice. Moreover, the deficiency of MyD88 (myeloid differentiation primary-response protein 88), a key mediator of TLR4, reduced the rupture rate. These findings suggest that the TLR4 pathway promotes the development of intracranial aneurysmal rupture by accelerating inflammation in aneurysmal walls. Inhibition of the TLR4 pathway in inflammatory cells may be a promising approach for the prevention of aneurysmal rupture and subsequent subarachnoid hemorrhage.

Noninvasive Vagus Nerve Stimulation Prevents Ruptures and Improves Outcomes in a Model of Intracranial Aneurysm in Mice.

Background and Purpose- Inflammation is a critical determinant of aneurysmal wall destabilization, growth, and rupture risk. Targeting inflammation may suppress aneurysm rupture. Vagus nerve stimulation (VNS) has been shown to suppress inflammation both systemically and in the central nervous system. Therefore, we tested the effect of a novel noninvasive transcutaneous VNS approach on aneurysm rupture and outcome in a mouse model of intracranial aneurysm formation with wall inflammation. Methods- Aneurysms were induced by a single stereotaxic injection of elastase into the cerebrospinal fluid at the skull base, combined with systemic deoxycorticosterone-salt hypertension, without or with high-salt diet, for mild or severe outcomes, respectively. Cervical VNS (two 2-minute stimulations 5 minutes apart) was delivered once a day starting from the day after elastase injection for the duration of follow-up. Transcutaneous stimulation of the femoral nerve (FNS) served as control. Multiple aneurysms developed in the circle of Willis and its major branches, resulting in spontaneous ruptures and subarachnoid hemorrhage, neurological deficits, and mortality. Results- In the milder model, VNS significantly reduced aneurysm rupture rate compared with FNS (29% versus 80%, respectively). Subarachnoid hemorrhage grades were also lower in the VNS group. In the more severe model, both VNS and FNS arms developed very high rupture rates (77% and 85%, respectively). However, VNS significantly improved the survival rate compared with FNS after rupture (median survival 13 versus 6 days, respectively), without diminishing the subarachnoid hemorrhage grades. Chronic daily VNS reduced MMP-9 (matrix metalloproteinase-9) expression compared with FNS, providing a potential mechanism of action. As an important control, chronic daily VNS did not alter systemic arterial blood pressure compared with FNS. Conclusions- VNS can reduce aneurysm rupture rates and improve the outcome from ruptured aneurysms.

Extracranial-Intracranial Bypass for Cerebral Vasculitis After Graft-Versus-Host Disease: Case Report and Review of the Literature.

BACKGROUND: Cerebral vasculitis owing to chronic graft-versus-host disease (GVHD) is very rare. To our knowledge, only 2 cases have been reported. We describe the first case of superficial temporal artery-middle cerebral artery (STA-MCA) bypass for cerebral vasculitis owing to GVHD. CASE DESCRIPTION: A 59-year-old woman presented with right upper extremity weakness and dysarthria 33 months after undergoing matching allogenic bone marrow transplantation. The patient had STA-MCA bypass for MCA occlusion and resting cerebral blood flow in the left MCA area improved. CONCLUSIONS: Although the mechanism of cerebral vasculitis after chronic GVHD is not known, cerebral vasculitis that causes cerebrovascular disease long after bone marrow transplantation should be considered. In this case, an STA-MCA bypass was efficient for the repeated ischemic attacks owing to cerebral vasculitis. Moreover, it is important to select the optimal recipient vessels to area originated neurologic symptoms.

Roles of Nicotine in the Development of Intracranial Aneurysm Rupture.

Background and Purpose- Tobacco cigarette smoking is considered to be a strong risk factor for intracranial aneurysmal rupture. Nicotine is a major biologically active constituent of tobacco products. Nicotine's interactions with vascular cell nicotinic acetylcholine receptors containing α7 subunits (α7*-nAChR) are thought to promote local inflammation and sustained angiogenesis. In this study, using a mouse intracranial aneurysm model, we assessed potential contributions of nicotine exposure and activation of α7*-nAChR to the development of aneurysmal rupture. Methods- Intracranial aneurysms were induced by a combination of deoxycorticosterone-salt induced hypertension and a single-dose elastase injection into cerebrospinal fluid in mice. Results- Exposure to nicotine or an α7*-nAChR-selective agonist significantly increased aneurysm rupture rate. Coexposure to an α7*-nAChR antagonist abolished nicotine's deleterious effect. In addition, nicotine's promotion of aneurysm rupture was absent in smooth muscle cell-specific α7*-nAChR subunit knockout mice but not in mice lacking α7*-nAChR on endothelial cells or macrophages. Nicotine treatment increased the mRNA levels of vascular endothelial growth factor, platelet-derived growth factor-B, and inflammatory cytokines. α7*-nAChR antagonist reversed nicotine-induced upregulation of these growth factors and cytokines. Conclusions- Our findings indicate that nicotine exposure promotes aneurysmal rupture through actions on vascular smooth muscle cell α7*-nAChR.

Prevention Effect of Antiplatelets on Aneurysm Rupture in a Mouse Intracranial Aneurysm Model.

BACKGROUND AND PURPOSE: Subarachnoid hemorrhage (SAH) from intracranial aneurysm rupture results in significant morbidity and mortality. In the present study, we examined the effect of most widely used antiplatelet drugs, aspirin and cilostazol, on aneurysm rupture prevention using a mouse intracranial aneurysm model. MATERIALS AND METHODS: Intracranial aneurysms were induced by a combination of deoxycorticosterone acetate-salt and a single injection of elastase into the cerebrospinal fluid in mice. Treatment with aspirin or cilostazol was started 1 day after aneurysm induction. Aneurysm rupture was detected by neurological symptoms and the presence of intracranial aneurysm with SAH was confirmed by post-mortem examination. RESULTS: Aspirin (10 mg/kg) significantly reduced aneurysm rupture (control:aspirin = 80%:31%, p < 0.05) without affecting the overall incidence of aneurysm formation (60%:62%). Cilostazol (3 mg/kg, 30 mg/kg) did not reduce both rupture rate (control:3 mg/kg:30 mg/kg = 81%:67%:77%) and the overall incidence of aneurysm formation (control:3 mg/kg:30 mg/kg = 72%:71%:76%). Tail vein bleeding time prolonged significantly in both aspirin and cilostazol groups (p < 0.01). CONCLUSION: Aspirin prevented aneurysm rupture in a mouse intracranial aneurysm model, while cilostazol did not. Aspirin, the most frequently used drug for patients with ischemic myocardial and cerebral diseases, is also effective in preventing cerebral aneurysmal rupture.

Protective Effect of Mesenchymal Stem Cells Against the Development of Intracranial Aneurysm Rupture in Mice.

BACKGROUND: Mesenchymal stem cells (MSCs) are multipotent stem or stromal cells found in multiple tissues. Intravenous MSC injections have been used to treat various diseases with an inflammatory component in animals and humans. Inflammation is emerging as a key component of pathophysiology of intracranial aneurysms. Modulation of inflammation by MSCs may affect sustained inflammatory processes that lead to aneurysmal rupture. OBJECTIVE: To assess the effect of MSCs on the development of aneurysm rupture using a mouse model. METHODS: Intracranial aneurysms were induced with a combination of a single elastase injection into the cerebrospinal fluid and deoxycorticosterone acetate salt-induced hypertension in mice. We administered allogeneic bone marrow-derived MSCs or vehicle, 6 and 9 d after aneurysm induction. RESULTS: MSC administration significantly reduced rupture rate (vehicle control vs MSCs, 90% vs 36%; P < .05). In cell culture experiments with an MSC and mast cell coculture, MSCs stabilized mast cells through cyclooxygenase-2 (COX-2)-dependent production of prostaglandin E2, thereby reducing the release of proinflammatory cytokines from mast cells. Pretreatment of MSCs with COX-2 inhibitor, NS-398, abolished the protective effect of MSCs against the development of aneurysm rupture. CONCLUSION: Intravenous administration of MSCs after aneurysm formation prevented aneurysmal rupture in mice. The protective effect of MSCs against the development of aneurysm rupture appears to be mediated in part by the stabilization of mast cells by MSCs.

Cerebellar Hemorrhage due to a Direct Carotid-Cavernous Fistula after Surgery for Maxillary Cancer.

Infratentorial cerebral hemorrhage due to a direct carotid-cavernous fistula (CCF) is very rare. To our knowledge, only four such cases have been reported. Cerebellar hemorrhage due to a direct CCF has not been reported. We describe a 63-year-old female who presented with reduced consciousness 3 days after undergoing a maxillectomy for maxillary cancer. Computed tomography showed a cerebellar hemorrhage. Magnetic resonance angiography showed a left-sided direct CCF draining into the left petrosal and cerebellar veins through the left superior petrosal sinus (SPS). Her previous surgery had sacrificed the pterygoid plexus and facial vein. Increased blood flow and reduced drainage could have led to increased venous pressure in infratentorial veins, including the petrosal and cerebellar veins. The cavernous sinus has several drainage routes, but the SPS is one of the most important routes for infratentorial venous drainage. Stenosis or absence of the posterior segment of the SPS can also result in increased pressure in the cerebellar and pontine veins. We emphasize that a direct CCF with cortical venous reflux should be precisely evaluated to determine the hemodynamic status and venous drainage from the cavernous sinus.

Human Mesenchymal Stem Cell-Derived Microvesicles Prevent the Rupture of Intracranial Aneurysm in Part by Suppression of Mast Cell Activation via a PGE2-Dependent Mechanism.

Activation of mast cells participates in the chronic inflammation associated with cerebral arteries in intracranial aneurysm formation and rupture. Several studies have shown that the anti-inflammatory effect of mesenchymal stem cells (MSCs) is beneficial for the treatment of aneurysms. However, some long-term safety concerns exist regarding stem cell-based therapy for clinical use. We investigated the therapeutic potential of microvesicles (MVs) derived from human MSCs, anuclear membrane bound fragments with reparative properties, in preventing the rupture of intracranial aneurysm in mice, particularly in the effect of MVs on mast cell activation. Intracranial aneurysm was induced in C57BL/6 mice by the combination of systemic hypertension and intrathecal elastase injection. Intravenous administration of MSC-derived MVs on day 6 and day 9 after aneurysm induction significantly reduced the aneurysmal rupture rate, which was associated with reduced number of activated mast cells in the brain. A23187-induced activation of both primary cultures of murine mast cells and a human mast cell line, LAD2, was suppressed by MVs treatment, leading to a decrease in cytokine release and tryptase and chymase activities. Upregulation of prostaglandin E2 (PGE2) production and E-prostanoid 4 (EP4) receptor expression were also observed on mast cells with MVs treatment. Administration of an EP4 antagonist with the MVs eliminated the protective effect of MVs against the aneurysmal rupture in vivo. Human MSC-derived MVs prevented the rupture of intracranial aneurysm, in part due to their anti-inflammatory effect on mast cells, which was mediated by PGE2 production and EP4 activation. Stem Cells 2016;34:2943-2955.

Successful serial imaging of the mouse cerebral arteries using conventional 3-T magnetic resonance imaging.

Serial imaging studies can be useful in characterizing the pathologic and physiologic remodeling of cerebral arteries in various mouse models. We tested the feasibility of using a readily available, conventional 3-T magnetic resonance imaging (MRI) to serially image cerebrovascular remodeling in mice. We utilized a mouse model of intracranial aneurysm as a mouse model of the dynamic, pathologic remodeling of cerebral arteries. Aneurysms were induced by hypertension and a single elastase injection into the cerebrospinal fluid. For the mouse cerebrovascular imaging, we used a conventional 3-T MRI system and a 40-mm saddle coil. We used non-enhanced magnetic resonance angiography (MRA) to detect intracranial aneurysm formation and T2-weighted imaging to detect aneurysmal subarachnoid hemorrhage. A serial MRI was conducted every 2 to 3 days. MRI detection of aneurysm formation and subarachnoid hemorrhage was compared against the postmortem inspection of the brain that was perfused with dye. The imaging times for the MRA and T2-weighted imaging were 3.7±0.5 minutes and 4.8±0.0 minutes, respectively. All aneurysms and subarachnoid hemorrhages were correctly identified by two masked observers on MRI. This MRI-based serial imaging technique was useful in detecting intracranial aneurysm formation and subarachnoid hemorrhage in mice.