scholarly journals Disruption of P2X4 purinoceptor and suppression of the inflammation associated with cerebral aneurysm formation

2019 ◽  
pp. 1-13 ◽  
Author(s):  
Miyuki Fukuda ◽  
Shunichi Fukuda ◽  
Joji Ando ◽  
Kimiko Yamamoto ◽  
Naohiro Yonemoto ◽  
...  
Keyword(s):  
Shear Stress ◽  
Cerebral Aneurysm ◽  
Arterial Wall ◽  
Quantitative Polymerase Chain Reaction ◽  
Cerebral Aneurysms ◽  
Artery Ligation ◽  
Hemodynamic Stress ◽  
Aneurysm Formation ◽  
Aneurysm Development ◽  
Cox 2

OBJECTIVEThere are no effective therapeutic drugs for cerebral aneurysms, partly because the pathogenesis remains unresolved. Chronic inflammation of the cerebral arterial wall plays an important role in aneurysm formation, but it is not clear what triggers the inflammation. The authors have observed that vascular endothelial P2X4 purinoceptor is involved in flow-sensitive mechanisms that regulate vascular remodeling. They have thus hypothesized that shear stress–associated hemodynamic stress on the endothelium causes the inflammatory process in the cerebral aneurysm development.METHODSTo test their hypothesis, the authors examined the role of P2X4 in cerebral aneurysm development by using P2X4−/− mice and rats that were treated with a P2X4 inhibitor, paroxetine, and subjected to aneurysm-inducing surgery. Cerebral aneurysms were induced by unilateral carotid artery ligation and renovascular hypertension.RESULTSThe frequency of aneurysm induction evaluated by light microscopy was significantly lower in the P2X4−/− mice (p = 0.0488) and in the paroxetine-treated male (p = 0.0253) and female (p = 0.0204) rats compared to control mice and rats, respectively. In addition, application of paroxetine from 2 weeks after surgery led to a significant reduction in aneurysm size in the rats euthanized 3 weeks after aneurysm-inducing surgery (p = 0.0145), indicating that paroxetine suppressed enlargement of formed aneurysms. The mRNA and protein expression levels of known inflammatory contributors to aneurysm formation (monocyte chemoattractant protein–1 [MCP-1], interleukin-1β [IL-1β], tumor necrosis factor–α [TNFα], inducible nitric oxide synthase [iNOS], and cyclooxygenase-2 [COX-2]) were all significantly elevated in the rats that underwent the aneurysm-inducing surgery compared to the nonsurgical group, and the values in the surgical group were all significantly decreased by paroxetine administration according to quantitative polymerase chain reaction techniques and Western blotting. Although immunolabeling densities for COX-2, iNOS, and MCP-1 were not readily observed in the nonsurgical mouse groups, such densities were clearly seen in the arterial wall of P2X4+/+ mice after aneurysm-inducing surgery. In contrast, in the P2X4−/− mice after the surgery, immunolabeling of COX-2 and iNOS was not observed in the arterial wall, whereas that of MCP-1 was readily observed in the adventitia, but not the intima.CONCLUSIONSThese data suggest that P2X4 is required for the inflammation that contributes to both cerebral aneurysm formation and growth. Enhanced shear stress–associated hemodynamic stress on the vascular endothelium may trigger cerebral aneurysm development. Paroxetine may have potential for the clinical treatment of cerebral aneurysms, given that this agent exhibits efficacy as a clinical antidepressant.

Abstract TP78: Down-regulation Of Vascular Na+/k+ ATPase In Oophorectomized Rats Feeding A High Salt Diet Is Associated With The Cerebral Aneurysm Formation

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Nobuhisa Matsushita ◽  
Yoshiteru Tada ◽  
Kenji Yagi ◽  
Keiko T Kitazato ◽  
Kenji Shimada ◽  
...  
Keyword(s):  
Cerebral Aneurysm ◽  
Efflux Pump ◽  
Cerebral Aneurysms ◽  
The Body ◽  
High Salt ◽  
Artery Ligation ◽  
High Salt Diet ◽  
Salt Diet ◽  
Aneurysm Formation ◽  
Water Ratio

Background and Purpose— Hypertension is thought to be associated with a high incidence of stroke. However, not all patients with unruptured cerebral aneurysms are hypertensive. In the DOCA-salt rats the increase in body water-free Na+ storage associated with hypertension is suggested. We hypothesized that in oophorectomized rats fed a high salt diet, body water-free Na+ accumulation may be increased, leading to the formation of cerebral aneurysms. To address the relationship between the increase in the body Na+-to-water ratio that characterizes water-free Na+ accumulation and the formation of cerebral aneurysms, we focused on vascular Na efflux pump Na+/K+ ATPase. Methods— Thirteen-week old female Sprague-Dawley rats subjected to carotid artery ligation were fed a high-salt diet and divided into 3 groups; a group without- (HSD) and another with bilateral oophorectomy (HSD/OVX) and a 3rd group that underwent additional renal artery ligation (HSD/OVX/RL) to induce hypertension. Results— Compared to HSD rats, the incidence of cerebral aneurysms and the body Na+-to-water ratio were significantly higher in HSD/OVX- and HSD/OVX/RL rats independent of hypertension. In their aneurysmal wall, ATP1α2, a subtype of Na+/K+-ATPase were down-regulated and renin-angiotensin system- and inflammation related molecules were up-regulated. In HSD/OVX/RL rats treatment with low dose olmesartan up-regulated ATP1α2 without affecting blood pressure and reduced the body Na+-to-water ratio and the incidence of cerebral aneurysm formation. Conclusions— These results suggest that a reduction in the vascular Na efflux pump during excessive salt intake in oophorectomized rats may be associated with the increase in water-free Na+ accumulation directing to cerebral aneurysm formation.

Association between semicarbazide-sensitive amine oxidase, a regulator of the glucose transporter, and elastic lamellae thinning during experimental cerebral aneurysm development

2008 ◽  
Vol 108 (3) ◽  
pp. 558-566 ◽  
Author(s):  
Igor Sibon ◽  
Nathalie Mercier ◽  
Danièle Darret ◽  
Patrick Lacolley ◽  
Jean-Marie Daniel Lamazière
Keyword(s):  
Smooth Muscle ◽  
Cerebral Aneurysm ◽  
Arterial Wall ◽  
Glucose Transporter ◽  
Amine Oxidase ◽  
Smooth Muscle Actin ◽  
Cerebral Arteries ◽  
Amine Oxidases ◽  
Artery Ligation ◽  
Aneurysm Development

Object Amine oxidases play a key role in the polymerization and cross-linking of the collagens and elastic lamellae of the arterial wall. The loss of elastic lamellae integrity is one of the first steps in the genesis of a cerebral aneurysm. The authors investigated the relation between semicarbazide-sensitive amine oxidase (SSAO) and the organization of the cerebral arterial wall during aneurysm development. Methods Intracranial aneurysms were induced in rats via unilateral carotid artery ligation and renovascular hypertension. This modified Hashimoto model was used to create elevated blood pressure associated with shear stress in cerebral arteries. The authors immunohistologically investigated some markers of the extracellular matrix (Types I, III, and IV collagen and elastin), vascular smooth muscle cell differentiation (smooth muscle myosin heavy chain [sm-MHC], α–smooth muscle actin, and desmin), and amine oxidases (SSAO and lysyl oxidase [LOX]) in the cerebral arterial wall in control and treated rats 1, 2, 3, 4, and 6 months after the surgical procedure. Results The authors found severe disorganization and thinning of the elastic lamellae and a dramatic reduction in SSAO activity and immunostaining during cerebral aneurysm development. In contrast, LOX markers were slightly increased. Elastic lamellae thinning was highly correlated with decreases in SSAO (r = 0.76, p < 0.0001). There was also a correlation between sm-MHC and SSAO levels. Conclusions The data suggested that cerebral hemodynamic modifications induce decreases in SSAO activity resulting in cell dedifferentiation and inducing dysregulation of glucose transport.

scholarly journals Role of diet-related factors in cerebral aneurysm formation and rupture

2019 ◽  
pp. 119-126
Author(s):  
Anna Czekajło
Keyword(s):  
Blood Pressure ◽  
Cerebral Aneurysm ◽  
Cerebral Aneurysms ◽  
Renin Angiotensin System ◽  
Vascular Wall ◽  
Caffeine Consumption ◽  
Related Factors ◽  
Hemodynamic Stress ◽  
Aneurysm Formation

Cerebral aneurysms (CAs) are dilations of the wall of an artery in the brain filled with blood. The prevalence of unrupted CA in general population is estimated at approximately 3%. Ruptured aneurysms are the cause of 85% of spontaneous subarachnoid hemorrhage (SAH) cases. The formation of cerebral aneurysms results from various factors, including chronic inflammation, hemodynamic stress and vascular wall remodeling. Reactive oxygen species may induce the endothelial dysfunction possibly through the activation of Nuclear Factor Kappa-B, which is a key regulator of the proinflammatory genes. Hypertension may additionally increase the hemodynamic stress and activate the local renin-angiotensin system. The aim of this review was to assess the role of selected diet-related factors in the formation and rupture of cerebral aneurysms. It appears that inadequate intake of dietary antioxidants, hyperhomocysteinemia, hypertension (including incidental elevated blood pressure) and alcohol consumption may increase the risk of intracranial aneurysms. Individuals at high risk of CA formation and/or rupture should consume adequate amounts of antioxidant vitamins (vitamin C, vitamin E and carotenoids), B vitamins (vitamin B6, vitamin B12 and folate), flavonoids and n-3 fatty acids, limit alcohol and caffeine consumption and regularly control their blood pressure. Vegetables, fruits, grains, pulses, nuts and fish, as well as herbs, spices and tea, should be the major components of the daily diet. Due to the synergistic effect of various dietary components on health, Mediterranean diet or Dietary Approach to Stop Hypertension (DASH) diet, as they meet abovementioned requirements and have high anti-inflammatory potential, are thus recommended for the prevention of cerebral aneurysm formation and rupture.

scholarly journals Potential Role of Aspirin in the Prevention of Aneurysmal Subarachnoid Hemorrhage

2015 ◽  
Vol 39 (5-6) ◽  
pp. 332-342 ◽  
Author(s):  
Robert M. Starke ◽  
Nohra Chalouhi ◽  
Dale Ding ◽  
David M. Hasan
Keyword(s):  
Cerebral Aneurysm ◽  
Peripheral Blood ◽  
Cerebral Aneurysms ◽  
Aneurysm Rupture ◽  
Aspirin Therapy ◽  
Blood Samples ◽  
Aneurysm Formation ◽  
Number Of Patients ◽  
Increased Risk ◽  
Cox 2

Background: Inflammation is a key element behind the pathophysiology of cerebral aneurysm formation and rupture. Aspirin is a potent inhibitor of cyclooxygenase-2 (COX), which plays a critical role in the expression of immune modulators known to contribute to cerebral aneurysm formation and rupture. Currently, there are no pharmacological therapies for patients with cerebral aneurysms. Both endovascular and microsurgical interventions may be associated with significant morbidity and mortality. Potentially, a medical alternative that prevents aneurysm progression and rupture may be a beneficial therapy for a significant number of patients. Summary: In animal models, treatment with aspirin and genetic inactivation of COX-2 decreases aneurysm formation and rupture. Selective inhibition of COX-1 did not decrease aneurysm rupture, suggesting that selection inhibition of COX-2 may be critical in thwarting aneurysm progression. Walls of ruptured human intracranial aneurysms have higher levels of COX-2 and microsomal prostaglandin E2 synthase 1 (mPGES-1), both of which are known to be inhibited by aspirin. In a pilot study, patients undergoing microsurgical clipping had attenuated expression of COX-2, mPGES-1, and macrophages in aneurysm walls after 3 months of aspirin therapy versus those that did not receive aspirin. Additionally, in patients undergoing endovascular therapy, local circulating expression of chemokines and COX-2 were increased in blood samples taken from within aneurysm domes as compared to peripheral blood sample controls. Treatment with aspirin also resulted in decreased expression of COX-2 within leukocytes within aneurysms as compared to peripheral blood samples. Novel molecular imaging with ferumoxytol-enhanced MRI may help in the identification of patients at increased risk for aneurysm rupture and assessment of a response to aspirin therapy. Key Messages: Aspirin has been found to be a safe in patients harboring cerebral aneurysms and clinical studies provide evidence that it may decrease the overall rate of rupture. Furthermore, aspirin is an accessible and inexpensive medicine for patients who may not have access to endovascular or microsurgical treatment or for patients who are deemed low risk of aneurysm rupture, high risk for intervention, or both. Future clinical trials are indicated to determine the overall effect of aspirin on aneurysm progression and rupture. This review provides an update on the potential mechanisms and benefits of aspirin in the treatment of cerebral aneurysms.

scholarly journals Blockade of the Platelet-Driven CXCL7-CXCR1/2 Pathway Prevents Cerebral Aneurysm Formation

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Kamil W Nowicki ◽  
Michael P D’Angelo ◽  
Wendy Fellows-Mayle ◽  
Michael M McDowell ◽  
Robert M Friedlander
Keyword(s):  
Cerebral Aneurysm ◽  
Small Molecule ◽  
Thrombus Formation ◽  
Vascular Inflammation ◽  
Cerebral Aneurysms ◽  
Artery Ligation ◽  
Aneurysm Formation ◽  
Carotid Artery Ligation ◽  
Molecule Inhibitor ◽  
Receptor Blockers

Abstract INTRODUCTION Platelet aggregation is intimately associated with vascular inflammation and is commonly seen on routine histology studies of cerebral aneurysms. Platelets, when activated, have been shown to augment neutrophil response and the proinflammatory cascade. Antiplatelet therapy, especially via ADP-GPIIb/IIIa antagonism, has inherent anti-inflammatory actions that could be of therapeutic interest in prevention of aneurysm formation, but could also interfere with healing of coiled aneurysms. Platelet-neutrophil complexes have been found to aggravate atherosclerosis through a positive feedback loop involving CXCL1, CXCR1/2, and CXCL7. We propose that treatment with GPIIb/IIIa antagonists or anti-CXCR1/2 receptor blockers could be used to prevent aneurysm formation. METHODS First, we induced cerebral aneurysm formation in a previously described intracranial aneurysm model via carotid artery ligation, hypertension, and stereotactic elastase injection in C57BL/6 mice, and analyzed vessels for lesion and thrombus formation. Raybiotech cytokines arrays were used to analyze 96 cytokines in induced aneurysms. Cerebral aneurysm formation was then studied in animals treated with 1:3 DMSO:PBS (control), clopidogrel, or anti-CXCR1/2 small molecule inhibitor. RESULTS CD31 + platelet aggregates are a common feature in human and mouse cerebral aneurysm specimens. Mice treated with 1 mg/kg clopidogrel develop significantly less aneurysms than controls (0% vs 57%, n = 6 and 7 respectively, P = .049). Semi-quantitative analysis of 96 different cytokines using Raybiotech arrays shows increased protein expression of CXCL7 in murine cerebral aneurysms when compared to controls. Treatment with clopidogrel results in reciprocal decrease in detected CXCL7. Targeting CXCL7-CXCR1/2 axis with 10 mg/kg reparixin (CXCR1/2 antagonist) tends decrease aneurysm formation. (14% vs 57%, n = 6 and 7, P = .13). CONCLUSION Small molecule inhibitors targeting platelet CXCL7-CXCR1/2 inflammatory axis can be used to prevent murine cerebral aneurysm formation.

Abstract WMP36: Inhibition of the Endothelial Shear Stress Sensor, P2x4 Purinoceptor Drastically Reduces Cerebral Aneurysm Formation

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Shunichi Fukuda ◽  
MIyuki Fukuda ◽  
Joji Ando ◽  
Kimiko Yamamoto ◽  
Tetsuya Tuskahara ◽  
...  
Keyword(s):  
Shear Stress ◽  
Cerebral Aneurysm ◽  
Knockout Mice ◽  
Wild Type ◽  
Internal Elastic Lamina ◽  
Aneurysm Formation ◽  
Shear Stress Sensor ◽  
Endothelial Shear Stress ◽  
Aneurysm Development ◽  
Elastic Lamina

Background and purpose: Although the assumption that wall shear stress-related hemodynamics is closely involved in cerebral aneurysm formation is now widely accepted, direct evidence still remains to be presented. Here, we examine a role of shear stress in cerebral aneurysm development, focused on a vascular endothelial shear sensor, P2X4 purinoceptor. Methods: P2X4 knockout mice and wild type mice were subjected to cerebral aneurysm-generating surgery with ligation of unilateral common carotid artery and renal hypertension. Damage to the internal elastic lamina, early phase aneurysm development, and the incidence of aneurysm induction were examined by light microscope. The expression of biochemical contributors to aneurysm formation was immunohistochemically examined. Additionally, the P2X4 purinoceptor inhibitor, paroxetine (10mg/kg/day) was administered to Sprague-Dawley rats after aneurysm-inducing surgery, and the incidence of aneurysm formation was examined. Results: Damage to the internal elastic lamina and the frequency of CA induction were significantly diminished in P2X4 knockout mice compared to control wild-type mice after CA-inducing surgery ( p =0.027 and 0.018, respectively). Expression levels of known contributors to aneurysm formation, iNOS, MCP-1, cathepsin L, and COX-2, were immunohistochemically weakened in P2X4 KO mice compared to wild-type mice. Moreover, paroxetine significantly attenuated the incidence of induced aneurysms in rats ( p =0.031). Conclusions: Disruption of the endothelial shear stress sensor, P2X4 purinoceptor drastically reduces cerebral aneurysm formation, suggesting that shear stress-related hemodynamics initiates cerebral aneurysm formation. The P2X4 purinoceptor inhibitor paroxetine, which is also prescribed to human as an antidepressant, may be a potential clinical prophylactic agent against cerebral aneurysm formation.

scholarly journals M1 macrophages are required for murine cerebral aneurysm formation

2017 ◽  
Vol 10 (1) ◽  
pp. 93-97 ◽  
Author(s):  
Kamil W Nowicki ◽  
Koji Hosaka ◽  
Frank J Walch ◽  
Edward W Scott ◽  
Brian L Hoh
Keyword(s):  
Cerebral Aneurysm ◽  
Macrophage Polarization ◽  
Cerebral Aneurysms ◽  
M2 Macrophage ◽  
Macrophage Phenotype ◽  
Aneurysm Formation ◽  
Inflammatory Phenotype ◽  
M1 Phenotype ◽  
Aneurysm Development ◽  
Over Time

IntroductionMacrophages and neutrophils have been separately implicated in cerebral aneurysm formation. The interactions between different myeloid subsets and the contributions of macrophage phenotypes in these lesions over time are not known. The purpose of the study was to examine macrophage phenotypic changes in cerebral aneurysms.MethodsWe induced aneurysm formation in C57BL/6 mice and quantified contributions of M1 and M2 macrophages in aneurysm specimens with or without neutrophil blockade. In our aneurysm model, the left common carotid and right renal arteries were ligated, and mice were placed on a hypertensive high fat diet. One week later, stereotactic injection with elastase solution into the basal cisterns was performed. An angiotensin II secreting osmotic pump was implanted. The mice were then treated with anti-CXCL1 antibody or IgG control antibody. Animals were euthanized at 3 days, or 1 or 2 weeks. The circle of Willis was analyzed using immunohistochemistry for M1 and M2 macrophage phenotype contributions.ResultsProinflammatory M1/M2 ratio increased in cerebral aneurysm formation over time, from 0.56 at 3 days to 1.75 at 2 weeks (p<0.0001). In contrast, anti-CXCL1 antibody blockade led to polarization towards an anti-inflammatory phenotype with an M1/M2 ratio of 0.95 at 2 weeks compared with IgG treated mice (p=0.0007).ConclusionsCXCL1 dependent neutrophil inflammation appears to have an important role in macrophage polarization to M1 phenotype in cerebral aneurysm development.

Histologically verified cerebral aneurysm formation secondary to embolism from cardiac myxoma

1995 ◽  
Vol 83 (1) ◽  
pp. 170-173 ◽  
Author(s):  
Kazuhide Furuya ◽  
Tomio Sasaki ◽  
Yuhei Yoshimoto ◽  
Yoshifumi Okada ◽  
Takamitsu Fujimaki ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Cardiac Tumor ◽  
Arterial Wall ◽  
Cardiac Myxoma ◽  
Cerebral Aneurysms ◽  
Surgical Removal ◽  
Arterial Aneurysm ◽  
Content Type ◽  
Aneurysm Formation ◽  
Aneurysm Wall

✓ Multiple aneurysm formation secondary to an embolism from the cardiac myxoma is a well-known phenomenon. The cerebral arterial aneurysm formation process involved remains to be elucidated, although occupation of the arterial wall by tumor cells has been proven histologically. The authors present the case of a patient in whom tumor cells in the aneurysm wall were demonstrated and penetration of viable myxoma cells into the wall was also observed 19 months after surgical removal of the cardiac tumor. Such findings have never before been verified histologically. In light of the histological findings, the authors discuss the therapeutic problems associated with cerebral aneurysms resulting from cardiac myxoma.

Abstract 107: Early Change in Ferumoxytol-Enhanced Magnetic Resonance Imaging Signal Suggests Unstable Human Cerebral Aneurysm. A Pilot Study

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
David M Hasan ◽  
donald hesitad
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Cerebral Aneurysm ◽  
Cerebral Aneurysms ◽  
Resonance Imaging ◽  
Unruptured Aneurysms ◽  
Ruptured Aneurysms ◽  
Cyclooxygenase 1 ◽  
Signal Changes ◽  
Cox 2

Background: Imaging with magnetic resonance imaging (MRI) 72 hours after infusion of ferumoxytol demonstrated maximal uptake by macrophages in the wall of human cerebral aneurysms. The clinical significance of early (i.e. within the first 24 hours) uptake of ferumoxytol by macrophages in the wall of human cerebral aneurysms is not clear. The purpose of this study was to determine whether early uptake of ferumoxytol which may indicate inflammation, suggests unstable cerebral aneurysm. Methods: 30 unruptured aneurysms in 22 patients were imaged with MRI 24 hours after infusion of ferumoxytol. Eighteen aneurysms were also imaged 72 hours after infusion of ferumoxytol. Aneurysm dome tissue was collected from four patients with early MRI signal changes, five patients with late signal changes, and five other patients with ruptured aneurysms. The tissue was immunostained for expression of cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), microsomal-prostaglandin-E2 synthase-1 (mPGES-1) and macrophages. Findings: In 23% (7/30) of aneurysms, there was pronounced early uptake of ferumoxytol. Four aneurysms were clipped. The remaining three aneurysms which were managed conservatively with observation, all ruptured within six months. In 89% (16/18) of aneurysms, there was pronounced uptake of ferumoxytol at 72 hours. Nine aneurysms were surgically clipped and nine were managed conservatively; none ruptured or increased in size in six months. With immunostaining, expression of COX-2, mPGES-1, and macrophages was similar in unruptured aneurysms with early uptake of ferumoxytol and ruptured aneurysms. Expression of these inflammatory molecules was significantly higher in aneurysms with early uptake of ferumoxytol than in aneurysms with late uptake. Interpretation: Uptake of ferumoxytol in aneurysm walls within the first 24 hours strongly suggests aneurysm instability and probability of rupture within six months, and may warrant intervention. Larger clinical studies are indicated to validate this preliminary observation.

Sign in / Sign up

Export Citation Format

Share Document