scholarly journals Vasa vasorum lumen narrowing in brain vascular hyalinosis in systemic hypertension patients with ischemic stroke

2020 ◽  
Author(s):  
Sergiy G. Gychka ◽  
Nataliia V. Shults ◽  
Sofia I. Nikolaienko ◽  
Lucia Marcocci ◽  
Nurefsan E. Sariipek ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Endothelial Cell ◽  
Protein Interactions ◽  
Actin Polymerization ◽  
Protein A ◽  
Vasa Vasorum ◽  
Postmortem Brain ◽  
Systemic Hypertension ◽  
Brain Vasculature ◽  
Lumen Narrowing

AbstractIschemic stroke is a major cause of death among patients with systemic hypertension. The narrowing of the lumen of the brain vasculature contributes to the increased incidence of stroke. While hyalinosis represents the major pathological lesions contributing to the vascular lumen narrowing and stroke, the pathogenic mechanism of brain vascular hyalinosis has not been well characterized. Thus, the present study examined the postmortem brain vasculature of human patients who died of ischemic stroke due to systemic hypertension. Hematoxylin and eosin staining and immunohistochemistry showed the occurrence of brain vascular hyalinosis with infiltrated plasma proteins along with the narrowing of vasa vasorum and oxidative stress. Transmission electron microscopy revealed the endothelial cell bulge protrusion into the vasa vasorum lumen and the occurrence of endocytosis in the vasa vasorum endothelium. The treatment of cultured microvascular endothelial cells with adrenaline also promoted the formation of the bulge as well as endocytic vesicles. siRNA knockdown of sortin nexin-9 (a mediator of clathrin-mediated endocytosis) inhibited the adrenaline-induced endothelial cell bulge formation. Adrenaline promoted protein-protein interactions between sortin nexin-9 and neural Wiskott–Aldrich Syndrome protein (a regulator of actin polymerization). We propose that endocytosis-depending endothelial cell bulge narrows the vasa vasorum, resulting in ischemic oxidative damage to the cerebral vessels, the formation of hyalinosis, the occurrence of ischemic stroke, and death in systemic hypertension patients.

scholarly journals Vasa Vasorum Lumen Narrowing in Brain Vascular Hyalinosis in Systemic Hypertension Patients Who Died of Ischemic Stroke

2020 ◽  
Vol 21 (24) ◽  
pp. 9611
Author(s):  
Sergiy G. Gychka ◽  
Nataliia V. Shults ◽  
Sofia I. Nikolaienko ◽  
Lucia Marcocci ◽  
Nurefsan E. Sariipek ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Ischemic Stroke ◽  
Endothelial Cell ◽  
Actin Polymerization ◽  
Vasa Vasorum ◽  
Postmortem Brain ◽  
Systemic Hypertension ◽  
Brain Vasculature ◽  
Cell Protrusion ◽  
Lumen Narrowing

Ischemic stroke is a major cause of death among patients with systemic hypertension. The narrowing of the lumen of the brain vasculature contributes to the increased incidence of stroke. While hyalinosis represents the major pathological lesions contributing to vascular lumen narrowing and stroke, the pathogenic mechanism of brain vascular hyalinosis has not been well characterized. Thus, the present study examined the postmortem brain vasculature of human patients who died of ischemic stroke due to systemic hypertension. Hematoxylin and eosin staining and immunohistochemistry showed the occurrence of brain vascular hyalinosis with infiltrated plasma proteins along with the narrowing of the vasa vasorum and oxidative stress. Transmission electron microscopy revealed endothelial cell bulge protrusion into the vasa vasorum lumen and the occurrence of endocytosis in the vasa vasorum endothelium. The treatment of cultured microvascular endothelial cells with adrenaline also promoted the formation of the bulge as well as endocytic vesicles. The siRNA knockdown of sortin nexin-9 (a mediator of clathrin-mediated endocytosis) inhibited adrenaline-induced endothelial cell bulge formation. Adrenaline promoted protein-protein interactions between sortin nexin-9 and neural Wiskott–Aldrich syndrome protein (a regulator of actin polymerization). Spontaneously hypertensive stroke-prone rats also exhibited lesions indicative of brain vascular hyalinosis, the endothelial cell protrusion into the lumen of the vasa vasorum, and endocytosis in vasa vasorum endothelial cells. We propose that endocytosis-dependent endothelial cell bulge protrusion narrows the vasa vasorum, resulting in ischemic oxidative damage to cerebral vessels, the formation of hyalinosis, the occurrence of ischemic stroke, and death in systemic hypertension patients.

Abstract TP276: Perlecan Is Required for the Maintenance of the Blood-Brain Barrier through the Interaction with Pericytes in a Mouse Ischemic Stroke Model

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Kuniyuki Nakamura ◽  
Tomoko Ikeuchi ◽  
Peipei Zhang ◽  
Craig Rhodes ◽  
Yuta Chiba ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Ischemic Stroke ◽  
Endothelial Cell ◽  
Blood Brain Barrier ◽  
Repair Process ◽  
Ischemic Lesion ◽  
Brain Vasculature ◽  
Integrin Α5 ◽  
The Brain

Introduction: The disruption of the blood-brain barrier (BBB) is a contributing factor for the deterioration of brain damages in ischemic stroke. Recent studies revealed that microvascular pericytes are involved in the maintenance of the BBB and in the repair process through platelet-derived growth factor receptor β (PDGFRβ), the expression of which is increased around the ischemic lesion. Here we focus on perlecan, the major heparan sulfate proteoglycan in the basement membrane (BM). It is expressed by endothelial cells in the brain and is implicated in many biological functions. In this report, we have studied the role of Perlecan in the BBB breakdown and in the subsequent repair process after ischemic stroke in a mouse model. We hypothesized that perlecan may play a protective role in the disruption of BBB through the interaction with pericytes after ischemic stroke. Methods: To elucidate the role of perlecan in the brain vasculature, we induced a 60-minute transient middle cerebral artery occlusion (MCAO) in adult conditional perlecan -deficient ( Perlecan -/- -Tg) mice, which express the perlecan transgene only in the cartilage to rescue the perinatal lethality of perlecan -deficient mice. Results: Although the BBB formation and function in the brain vasculature appeared to be unaffected in Perlecan -/- -Tg mice under healthy condition, Perlecan -/- -Tg mice demonstrated larger infarct volumes and more BBB leakage than control mice on post-surgery day (PSD) 2 after MCAO. Perlecan -/- -Tg mice exhibited less PDGFRβ-positive pericytes around the ischemic lesion on PSD 3 to 7 than control mice, suggesting that the perlecan deficiency suppressed pericyte activation. At a mechanistic level, integrin α5, a potential receptor for perlecan, was detectable in both endothelial cells and pericytes in the ischemic lesion, suggesting that endothelial cell-derived perlecan may regulate pericyte activation in response to ischemia through integrin α5. Conclusions: Our results suggest that perlecan is required for the activation of pericytes and thereby, contributing to the endothelial cell-pericyte integrity in the BBB maintenance after ischemic stroke.

scholarly journals A Computational Approach for Protein-Protein Interactions of Bacterial Surface Layer Protein with Human Erb3 and αIIB-β3 Receptors

2021 ◽  
Vol 12 (1) ◽  
pp. 420-430
Keyword(s):  
Surface Layer ◽  
Molecular Docking ◽  
Protein Interactions ◽  
Protein A ◽  
Computational Approach ◽  
Microbial Interactions ◽  
Protein Protein Interactions ◽  
Epithelial Surface ◽  
Surface Receptors ◽  
Surface Layer Protein

Host microbial interactions had significant factors in maintains homeostasis and immune-related activity. One such interaction made by Lactobacillus sp. with Surface layer proteins (Slps) had been studied through a computational approach. Erb3 and αIIB-β3, which are epithelial surface layer receptors, are subjected to interact with the Slp homology model. Both cell surface receptors were subjected to interact through computational docking, followed by molecular dynamics simulations through the coarse-grain method to explore the conformational stability. Through the implementation of the molecular docking for the surface layer protein A, we have shown the surface layer protein A, protein-protein interactions are higher in cellular receptors with epidermal growth factor receptor at an -34.45 ΔG and -51.19 ΔG through molecular docking with Erb3 and αIIB-β3. This study shows the unique interaction of Slp with the epithelial surface receptors like Erb3 and αIIB-β3, which are multipurpose applications in microbial-based drug therapeutics.

scholarly journals Sex Differences in Ischemic Stroke Outcomes in Patients With Pulmonary Hypertension

2021 ◽  
Author(s):  
Tiberiu A. Pana ◽  
Dana K. Dawson ◽  
Mohamed O. Mohamed ◽  
Fiona Murray ◽  
David L. Fischman ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Sex Differences ◽  
Ischemic Stroke ◽  
Hospital Mortality ◽  
Acute Ischemic Stroke ◽  
Systemic Hypertension ◽  
Stroke Outcomes ◽  
Female Patients ◽  
Prolonged Hospitalization ◽  
The Impact

Background The association between systemic hypertension and cerebrovascular disease is well documented. However, the impact of pulmonary hypertension (PH) on acute ischemic stroke outcomes is unknown despite PH being recognized as a risk factor for acute ischemic stroke. We aimed to determine the association between PH and adverse in‐hospital outcomes after acute ischemic stroke, as well as whether there are sex differences in this association. Methods and Results Acute ischemic stroke admissions from the US National Inpatient Sample between October 2015 and December 2017 were included. The relationship between PH and outcomes (mortality, prolonged hospitalization >4 days, and routine home discharge) was analyzed using logistic regressions adjusting for demographics, comorbidities, and revascularization therapies. Interaction terms between PH and sex and age groups were also included. A total of 221 249 records representative of 1 106 045 admissions were included; 2.9% of patients had co‐morbid PH, and 35.34% of those were male. PH was not associated with in‐hospital mortality (odds ratio [OR], 0.96; 95% CI, 0.86–1.09) but was associated with increased odds of prolonged hospitalization (OR, 1.15; 95% CI, 1.09–1.22) and decreased odds of routine discharge (OR, 0.87; 95% CI, 0.81–0.94) for both sexes. Older patients with PH were significantly less likely to be discharged routinely ( P =0.028) than their younger counterparts. Compared with female patients with PH, men were 31% more likely to die in hospital ( P =0.024). Conclusions PH was not significantly associated with in‐hospital mortality but was associated with prolonged hospitalization and adverse discharge status. Male patients with PH were more likely to die in hospital than female patients.

Risk of Ischemic Stroke in High Risk Atrial Fibrillation Patients during Periods of Warfarin Discontinuation for Surgical Procedures

2016 ◽  
Vol 42 (5-6) ◽  
pp. 346-351 ◽  
Author(s):  
Adnan I. Qureshi ◽  
Nauman Jahangir ◽  
Ahmed A. Malik ◽  
Mohammad Rauf Afzal ◽  
Fayyaz Orfi ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Atrial Fibrillation ◽  
Ischemic Stroke ◽  
High Risk ◽  
Surgical Procedures ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Systemic Hypertension ◽  
Ventricular Ejection Fraction

Importance: The risk of ischemic stroke during periods of warfarin discontinuation for surgical procedures is recognized but not well characterized. Objective: The study aimed to quantitate the risk of ischemic stroke associated with high risk atrial fibrillation during periods of warfarin discontinuation. Design, Setting and Participants: A cohort of 4,060 patients (mean follow-up period of 3.5 ± 1.3 years) were randomized into the Atrial Fibrillation Follow-Up Investigation of Rhythm Management study. Patients enrolled in the study had atrial fibrillation plus at least one other risk factor for stroke or death: age ≥65 years', systemic hypertension, diabetes mellitus, congestive heart failure, transient ischemic attack, prior stroke, left atrium >50 mm, left ventricular fractional shortening <25% or left ventricular ejection fraction <40%. Exposure: Warfarin discontinuation for procedure. Main Outcome and Measures: The association of warfarin discontinuation with the incidence of ischemic stroke using pooled repeated measures and Cox proportional hazards analyses during follow-up after adjusting for age, gender, obesity, diabetes mellitus, hypercholesterolemia, cigarette smoking and study period. Results: Warfarin discontinuation for procedure occurred in 265 (0.4%) of the 71,355 person observations. Compared with those without warfarin discontinuation, the rate of ischemic stroke was higher among participants with surgery-related warfarin discontinuation (1.1% of 265 person observations vs. 0.2% of 71,090 person observations, p = 0.001). Warfarin discontinuation was associated with an increased risk for ischemic stroke (relative risk 5.8; 95% CI 1.8-18.4) after adjusting for potential confounders. The population-attributable risk associated with surgery-related warfarin discontinuation was estimated to be 23.1% (95% CI 15.2-30.9%) for ischemic stroke. Conclusions and Relevance: The 6-fold higher risk of ischemic stroke associated with discontinuation of warfarin for surgical procedures must be recognized in high risk atrial fibrillation patients and considered in the risk-benefit analysis of any procedure.

Peptide5 attenuates rtPA related brain microvascular endothelial cells reperfusion injury via the Wnt/β-catenin signalling pathway

2021 ◽  
Vol 18 ◽  
Author(s):  
Weimin Ren ◽  
Chuyi Huang ◽  
Heling Chu ◽  
Yuping Tang ◽  
Xiaobo Yang
Keyword(s):  
Endothelial Cells ◽  
Ischemic Stroke ◽  
Endothelial Cell ◽  
Cell Injury ◽  
Time Window ◽  
Microvascular Endothelial Cells ◽  
Brain Microvascular Endothelial Cells ◽  
Endothelial Cell Injury ◽  
Endothelial Cell Death ◽  
Therapeutic Time Window

Aims: Brain vascular endothelial cell dysfunction after rtPA treatment is a significant factor associated with poor prognosis, suggesting that alleviation of rtPA-related endothelial cell injury may represent a potential beneficial strategy along with rtPA thrombolysis. Background: Thrombolysis with recombinant tissue plasminogen activator (rtPA) is beneficial for acute ischemic stroke but may increase the risk of hemorrhagic transformation (HT), which is considered ischemia-reperfusion injury. The underlying reason may contribute to brain endothelial injury and dysfunction related to rtPA against ischemic stroke. As previous studies have demonstrated that transiently blocked Cx43 using peptide5 (Cx43 mimetic peptide) during retinal ischemia reduced vascular leakage, it is necessary to know whether this might help decrease side effect of rtPA within the therapeutic time window. Objective: This study aims to investigate the effects of peptide5 on rtPA-related cell injury during hypoxia/reoxygenation (H/R) within the therapeutic time window. Methods: In this study, we established a cell hypoxia/reoxygenation H/R model in cultured primary rat brain microvascular endothelial cells (RBMECs) and evaluated endothelial cell death and permeability after rtPA treatment with or without transient peptide5. In addition, we also investigated the potential signaling pathway to explore the underlying mechanisms preliminarily. Results: The results showed that peptide5 inhibited rtPA-related endothelial cell death and permeability. It also slightly increased tight junction (ZO-1, occluding, claudin-5) and β-catenin mRNA expression, demonstrating that peptide5 might attenuate endothelial cell injury by regulating the Wnt/β-catenin pathway. The following bioinformatic exploration from the GEO dataset GSE37239 was also consistent with our findings. Conclusion: This study showed that the application of peptide5 maintained cell viability and permeability associated with rtPA treatment, revealing a possible pathway that could be exploited to limit rtPA-related endothelial cell injury during ischemic stroke. Furthermore, the altered Wnt/β-catenin signaling pathway demonstrated that signaling pathways associated with Cx43 might have potential applications in the future. This study may provide a new way to attenuate HT and assist the application of rtPA in ischemic stroke.

Abstract WP430: Endothelial Cell Collection from Ipsilateral Middle Cerebral Artery in Acute Ischemic Stroke

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Sunil A Sheth ◽  
Abhishek Verma ◽  
David S Liebeskind ◽  
Jeffrey L Saver ◽  
Gary Duckwiler ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Endothelial Cell ◽  
Middle Cerebral Artery ◽  
Acute Ischemic Stroke ◽  
Cerebral Artery ◽  
Critical Role ◽  
Early Time ◽  
Stent Retriever ◽  
Positive Controls

Introduction: The cerebrovascular endothelium plays a critical role in the pathogenesis of and response to acute ischemic stroke (AIS). To date, techniques to study its function have relied on animal and in vitro models. A robust method of endothelial cell (EC) capture in patients with AIS at early time points, from within the ischemic region, could greatly advance our understanding of cerebrovascular injury. Method: Patients undergoing thrombectomy for middle cerebral artery occlusion (MCA) within 8 hours of onset were offered enrollment if the pass of their stent-retriever device occurred directly into a distal access catheter in the proximal M1 segment, limiting exposure of the device to only the MCA. After retrieval, ECs adherent to the devices were retrieved and stained for EC (CD31) and leukocyte (CD45) markers. EC identity and yield were confirmed by flow cytometry with simultaneous immuno-fluorescence microscopy. Cultured human ECs were used as positive controls. The EC fraction was defined as CD31 + CD45 - with size and morphological features consistent with the positive controls. Results: ECs from stent-retriever devices (n=3) were collected and pooled. Approximately 8% of the collected cells represented ECs. EC collected from the stent-retrievers demonstrated highly similar shape, morphology and antibody staining patterns compared to the positive controls (Figure). Conclusions: Here we provide the first demonstration of a rapid post-thrombectomy method for reliable harvesting of cerebral ECs in humans. The ability to capture these cells in patients with AIS within hours of symptom onset opens many avenues of exploration for determining the role of ECs in AIS.

Noninvasive Detection of Misfolded Proteins in the Brain Using [11C]BF-227 PET

2013 ◽  
pp. 438-445
Author(s):  
Nobuyuki Okamura ◽  
Shozo Furumoto ◽  
Manabu Tashiro ◽  
Katsutoshi Furukawa ◽  
Hiroyuki Arai ◽  
...  
Keyword(s):  
Protein Misfolding ◽  
Protein A ◽  
Lewy Bodies ◽  
Protein Aggregates ◽  
Brain Regions ◽  
Postmortem Brain ◽  
In Vivo Detection ◽  
Misfolding Diseases ◽  
The Brain

Alzheimer’s disease (AD) and many other neurodegenerative disorders belong to the family of protein misfolding diseases. These diseases are characterized by the deposition of insoluble protein aggregates containing an enriched ß-sheet structure. To evaluate PET amyloid-imaging tracer [11C]BF-227 as an agent for in vivo detection of various kinds of misfolded protein, a [11C]BF-227 PET study was performed in patients with various protein misfolding diseases, including AD, frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), sporadic Creutzfeldt-Jakob disease (sCJD) and Gerstmann-Sträussler-Scheinker disease (GSS). BF-227 binds to ß-amyloid fibrils with high affinity. Most of the AD patients showed prominent retention of [11C]BF-227 in the neocortex. In addition, neocortical retention of BF-227 was observed in the subjects with mild cognitive impairment who converted to AD during follow-up. DLB patients had elevated [11C]BF-227 uptake in the neocortex. However, FTD and sCJD patients showed no cortical retention of [11C]BF-227. Patients with multiple system atrophy had elevated BF-227 binding in the putamen. Finally, GSS patients had elevated BF-227 uptake in the cerebellum and other brain regions. This chapter confirms that BF-227 can selectively bind to a-synuclein and prion protein deposits using postmortem brain samples. Based on these findings, [11C]BF-227 is not necessarily specific for ß-amyloid in AD patients. However, this tracer could be used to detect various types of protein aggregates in the brain.

Sign in / Sign up

Export Citation Format

Share Document