scholarly journals Medin aggregation causes cerebrovascular dysfunction in aging wild-type mice

2020 ◽  
Vol 117 (38) ◽  
pp. 23925-23931
Author(s):  
Karoline Degenhardt ◽  
Jessica Wagner ◽  
Angelos Skodras ◽  
Michael Candlish ◽  
Anna Julia Koppelmann ◽  
...  
Keyword(s):  
Healthy Aging ◽  
Vascular Dysfunction ◽  
Upper Body ◽  
Dependent Manner ◽  
Wild Type ◽  
Brain Vasculature ◽  
Cerebrovascular Function ◽  
Age Related ◽  
Novel Approach ◽  
Cerebrovascular Dysfunction

Medin is the most common amyloid known in humans, as it can be found in blood vessels of the upper body in virtually everybody over 50 years of age. However, it remains unknown whether deposition of Medin plays a causal role in age-related vascular dysfunction. We now report that aggregates of Medin also develop in the aorta and brain vasculature of wild-type mice in an age-dependent manner. Strikingly, genetic deficiency of the Medin precursor protein, MFG-E8, eliminates not only vascular aggregates but also prevents age-associated decline of cerebrovascular function in mice. Given the prevalence of Medin aggregates in the general population and its role in vascular dysfunction with aging, targeting Medin may become a novel approach to sustain healthy aging.

Abstract 123: Age-Related Endothelial Senescence is Driven by Thrombospondin-1-Activated NADPH Oxidase Nox1

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Daniel N Meijles ◽  
Imad Al Ghouleh ◽  
Sanghamitra Sahoo ◽  
Jefferson H Amaral ◽  
Heather Knupp ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Vascular Diseases ◽  
Dependent Manner ◽  
Wild Type ◽  
Molecular Control ◽  
Redox Biology ◽  
Age Related ◽  
P53 Activation

Organismal aging represents an independent risk factor underlying many vascular diseases, including systemic and pulmonary hypertension, and atherosclerosis. While the mechanisms driving aging are largely elusive, a steady persistent increase in tissue oxidative stress has been associated with senescence. Previously we showed TSP1 elicits NADPH oxidase (Nox)-dependent vascular smooth muscle cell oxidative stress. However mechanisms by which TSP1 affects endothelial redox biology are unknown. Here, we tested the hypothesis that TSP1 induces endothelial oxidative stress-linked senescence in aging. Using rapid autopsy disease-free human pulmonary (PA) artery, we identified a significant positive correlation between age, protein levels of TSP1, Nox1 and the cell-cycle repressor p21cip (p<0.05). Age also positively associated with increased Amplex Red-detected PA hydrogen peroxide levels (p<0.05). Moreover, treatment of human PA endothelial cells (HPAEC) with TSP1 (2.2nM; 24h) increased expression (~1.9 fold; p<0.05) and activation of Nox1 (~1.7 fold; p<0.05) compared to control, as assessed by Western blot and SOD-inhibitable cytochrome c reduction. Western blotting and immunofluorescence showed a TSP1-mediated increase in p53 activation, indicative of the DNA damage response. Moreover, TSP1 significantly increased HPAEC senescence in a p53/p21cip/Rb-dependent manner, as assessed by immunofluorescent detection of subcellular localization and senescence-associated β-galactosidase staining. To explore this pathway in vivo, middle-aged (8-10 month) wild-type and TSP1-null mice were utilized. In the TSP1-null, reduced lung senescence, oxidative stress, Nox1 levels and p21cip expression were observed compared to wild-type supporting findings in human samples and cell experiments. Finally, prophylactic treatment with specific Nox1 inhibitor NoxA1ds (10μM) attenuated TSP1-induced HPAEC ROS, p53 activation, p21cip expression and senescence. Taken together, our results provide molecular insight into the functional interplay between TSP1 and Nox1 in the regulation of endothelial senescence, with implications for molecular control of the aging process.

Depletion of microglia mitigates cerebrovascular dysfunction in diet-induced obesity mice

2021 ◽  
Author(s):  
Qing Shen ◽  
Guo Zhang
Keyword(s):  
Basilar Artery ◽  
Vascular Dysfunction ◽  
Underlying Mechanism ◽  
Diet Induced Obesity ◽  
Cerebrovascular Function ◽  
Cerebrovascular Dysfunction ◽  
Normal Body Weight ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
The Brain

Obesity is frequently associated with cerebrovascular dysfunction, however, the underlying mechanism remains less well understood. In this study, by using pharmacological approaches, we show that neuroinflammation involving microglia plays an important role in obesity-related cerebrovascular dysfunction. PLX3397 treatment, which leads to depletion of microglia, reduced the wall thickness and collagen deposition in the basilar artery of diet-induced obesity (DIO) mice. Besides, the phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177 was enhanced, suggesting improved endothelial function of the basilar artery. The wire myography data show that acetylcholine-elicited relaxation of basilar artery isolated from DIO mice was improved after the treatment with PLX3397. Moreover, our data demonstrate that brain administration of IL-18 impaired cerebrovascular function in mice with normal body weight. Together, these data suggest that neuroinflammation involving microglia is important in obesity-related vascular dysfunction in the brain.

scholarly journals INCREASED C3 IN THE AGING BRAIN PROMOTES INFLAMMATORY TRANSITION IN ENDOTHELIAL CELLS

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S840-S840
Author(s):  
Nicholas E Propson ◽  
Alexandra Litvinchuk ◽  
Ethan R Roy ◽  
Bianca Contreras ◽  
Wei Cao ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Disease Onset ◽  
Strong Relationship ◽  
Complement C3 ◽  
Aging Brain ◽  
Aged Mouse ◽  
Dependent Manner ◽  
Brain Vasculature ◽  
Age Related ◽  
Bbb Permeability

Abstract Innate immunity has been implicated in normal aging, and age-related disease. The connection between age-related neuroinflammation and change in brain vasculature prior to disease onset remains poorly understood. The complement pathway is an established mediator of neuroinflammation, and increased complement C3 is seen in the aging brain. Thus, we asked whether C3 can promote changes in brain vasculature. We found age dependent increase of brain C3 levels in C57BL/6J mice. Furthermore, we found an increase in expression of adhesion molecule VCAM-1 in endothelial cells (ECs) of the cortex and hippocampus, which was rescued in aged C3a receptor null (C3ar1-/-) mice and aged C3a receptor (C3aR) antagonist treated mice. We confirmed these results by qPCR analysis for Vcam1 in sorted ECs. Human brain microvascular endothelial cells (HBMECs) treated with C3a showed increased expression of VCAM-1, but not other adhesion molecules. Sorted ECs from C3ar1-/- mice challenged with LPS confirmed these findings. Furthermore, C3aR signaling in ECs showed increased blood-brain barrier (BBB) permeability using trans-endothelial electrical resistance (TEER), and BBB impermeable dye injections. HBMECs treated with C3a revealed mis-localization of VE-Cadherin, followed by reduction in protein level when analyzed by immunofluorescence, which promotes increased barrier permeability. As a functional consequence of VCAM-1 expression and increased BBB permeability we found aged mouse brains have increased peripheral lymphocyte (CD45+/CD11b-) infiltration, which was reduced in a C3aR dependent manner. In conclusion, our work suggests there is a strong relationship between C3 expression and vascular C3aR contributing to a functional transition in endothelial cells during aging.

scholarly journals Antioxidant Roles of Heme Oxygenase, Carbon Monoxide, and Bilirubin in Cerebral Circulation during Seizures

2012 ◽  
Vol 32 (6) ◽  
pp. 1024-1034 ◽  
Author(s):  
Helena Parfenova ◽  
Charles W Leffler ◽  
Shyamali Basuroy ◽  
Jianxiong Liu ◽  
Alexander L Fedinec
Keyword(s):  
Oxidative Stress ◽  
Carbon Monoxide ◽  
Heme Oxygenase ◽  
Vascular Dysfunction ◽  
Antioxidant Properties ◽  
Cerebrovascular Function ◽  
Cerebrovascular Dysfunction ◽  
Cobalt Protoporphyrin ◽  
Endogenous Antioxidant ◽  
The Brain

Postictal cerebrovascular dysfunction is an adverse effect of seizures in newborn piglets. The brain heme oxygenase (HO) provides protection against cerebrovascular dysfunction. We investigated the contribution of reactive oxygen species (ROS) to seizure-induced vascular damage and the mechanism of HO vasoprotection. In a bicuculline model of seizures, we addressed the hypotheses: (1) seizures increase brain ROS; (2) ROS contribute to cerebral vascular dysfunction; (3) ROS initiate a vasoprotective mechanisms by activating endogenous HO; and (4) HO products have antioxidant properties. As assessed by dihydroethidium oxidation (ox-DHE), seizures increased ROS in cerebral vessels and cortical astrocytes; ox-DHE elevation was prevented by tiron and apocynin. An HO inhibitor, tin protoporphyrin, potentiated, whereas an HO-1 inducer, cobalt protoporphyrin, blocked seizure-induced increase in DHE oxidation. Heme oxygenase products carbon monoxide (CO) (CORM-A1) and bilirubin attenuated ox-DHE elevation during seizures. Antioxidants tiron and bilirubin prevented the loss of postictal cerebrovascular dilations to bradykinin, glutamate, and sodium nitroprusside. Tiron and apocynin abrogated activation of the brain HO during seizures. Overall, these data suggest that long-term adverse cerebrovascular effects of seizures are attributed to oxidative stress. On the other hand, seizure-induced ROS are required for activation of the endogenous antioxidant HO/CO/bilirubin system that alleviates oxidative stress-induced loss of postictal cerebrovascular function in piglets.

scholarly journals Brain Vasculature and Cognition

2019 ◽  
Vol 39 (4) ◽  
pp. 593-602 ◽  
Author(s):  
Abdelrahman Y. Fouda ◽  
Susan C. Fagan ◽  
Adviye Ergul
Keyword(s):  
Cognitive Impairment ◽  
Intervention Strategies ◽  
Proper Function ◽  
Cerebral Vasculature ◽  
Brain Vasculature ◽  
Cerebrovascular Function ◽  
Cerebrovascular Dysfunction ◽  
Function Preservation ◽  
Almost All ◽  
The Brain

There is a complex interaction between the brain and the cerebral vasculature to meet the metabolic demands of the brain for proper function. Preservation of cerebrovascular function and integrity has a central role in this sophisticated communication within the brain, and any derangements can have deleterious acute and chronic consequences. In almost all forms of cognitive impairment, from mild to Alzheimer disease, there are changes in cerebrovascular function and structure leading to decreased cerebral blood flow, which may initiate or worsen cognitive impairment. In this focused review, we discuss the contribution of 2 major vasoactive pathways to cerebrovascular dysfunction and cognitive impairment in an effort to identify early intervention strategies.

scholarly journals Apolipoprotein E4 mediates insulin resistance-associated cerebrovascular dysfunction and the post-prandial response

2017 ◽  
Vol 39 (5) ◽  
pp. 770-781 ◽  
Author(s):  
Lance A Johnson ◽  
Eileen Ruth Torres ◽  
Sydney Weber Boutros ◽  
Esha Patel ◽  
Tunde Akinyeke ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cerebral Blood Volume ◽  
Cerebral Metabolism ◽  
Metabolic Dysfunction ◽  
Cerebrovascular Function ◽  
Age Related ◽  
Increased Risk ◽  
Cerebrovascular Dysfunction ◽  
Potential Link ◽  
Age Related Cognitive Decline

Metabolic dysfunction, commonly a result of diets high in saturated fats and sugar, is associated with impaired cognitive function and an increased risk of age-related cognitive decline (ACD) and Alzheimer’s disease (AD). Compared to the E3 isoform of apolipoprotein (apoE), the E4 isoform is a major genetic risk factor for ACD, AD, and for developing cognitive impairments following various environmental challenges, including dietary challenges such as a high-fat diet (HFD). Both insulin resistance (IR) and E4 are associated with metabolic and vascular impairments. Deficits in cerebral metabolism and cerebrovascular function have been proposed as initiating events leading to these impairments. In the current study, we employed a model of human apoE targeted replacement mice and HFD-induced obesity to study the potential link between E4 and IR, at rest and following a postprandial challenge. HFD-induced IR was associated with impaired cognition, reduced cerebral blood volume and decreased glucose uptake. These effects were more profound in E4 than E3 mice. Furthermore, the cognitive, metabolic and cerebrovascular responses to an exogenous glucose load showed an apoE isoform-dependent response, with E4, but not E3 mice, acutely benefiting from a spike in blood glucose.

scholarly journals BECN1 F121A mutation increases autophagic flux in aged mice and improves aging phenotypes in an organ-dependent manner

2022 ◽  
Author(s):  
Salwa Sebti ◽  
Zhongju Zou ◽  
Michael U Shiloh
Keyword(s):  
Skeletal Muscle ◽  
Model Organisms ◽  
Autophagic Flux ◽  
Dependent Manner ◽  
Multiple Model ◽  
Wild Type ◽  
Age Related ◽  
Organ Specific ◽  
Muscle Fiber Atrophy ◽  
Fiber Atrophy

Autophagy is necessary for lifespan extension in multiple model organisms and autophagy dysfunction impacts age-related phenotypes and diseases. Introduction of an F121A mutation into the essential autophagy protein BECN1 constitutively increases basal autophagy in young mice and reduces cardiac and renal age-related changes in longer-lived Becn1F121A mutant mice. However, both autophagic and lysosomal activity have been described to decline with age. Thus, whether autophagic flux is maintained during aging and whether it is enhanced in Becn1F121A mice is unknown. Here we demonstrate that old wild type mice maintained functional autophagic flux in heart, kidney and skeletal muscle but not liver, and old Becn1F121A mice had increased autophagic flux in those same organs compared to wild type. In parallel, Becn1F121A mice were not protected against age-associated hepatic phenotypes but demonstrated reduced skeletal muscle fiber atrophy. These findings identify an organ-specific role for the ability of autophagy to impact organ aging phenotypes.

Sex- and age-related differences in the chronic pressure-natriuresis relationship: role of the angiotensin type 2 receptor

2014 ◽  
Vol 307 (8) ◽  
pp. F901-F907 ◽  
Author(s):  
Katrina M. Mirabito ◽  
Lucinda M. Hilliard ◽  
Michelle M. Kett ◽  
Russell D. Brown ◽  
Sean C. Booth ◽  
...  
Keyword(s):  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Receptor Expression ◽  
Dependent Manner ◽  
Wild Type ◽  
Age Related ◽  
Angiotensin Type 2 Receptor ◽  
Pressure Natriuresis ◽  
Angiotensin Type

Sex hormones regulate the renin-angiotensin system. For example, estrogen enhances expression of the angiotensin type 2 receptor. We hypothesized that activation of the angiotensin type 2 receptor shifts the chronic pressure-natriuresis relationship leftward in females compared with males and that this effect is lost with age. Mean arterial pressure was measured by radiotelemetry in adult (4 mo old) and aged (14 mo old) wild-type and angiotensin type 2 receptor knockout male and female mice. Chronic pressure-natriuresis curves were constructed while mice were maintained on a normal-salt (0.26%) diet and following 6 days of high salt (5.0%) diet. Mean arterial pressure was lower in adult wild-type females than males (88 ± 1 and 97 ± 1 mmHg, respectively), a difference that was maintained with age, but was absent in adult knockout mice. In wild-type females, the chronic pressure-natriuresis relationship was shifted leftward compared with knockout females, an effect that was lost with age. In males, the chronic pressure-natriuresis relationship was not influenced by angiotensin type 2 receptor deficiency. Compared with age-matched females, the chronic pressure-natriuresis relationships in male mice were shifted rightward. Renal expression of the angiotensin type 2 receptor was fourfold greater in adult wild-type females than males. With age, the angiotensin type 2 receptor-to-angiotensin type 1 receptor balance was reduced in females. Conversely, in males, angiotensin receptor expression did not vary significantly with age. In conclusion, the angiotensin type 2 receptor modulates the chronic pressure-natriuresis relationship in an age- and sex-dependent manner.

scholarly journals Spatial Memory and Microglia Activation in a Mouse Model of Chronic Neuroinflammation and the Anti-inflammatory Effects of Apigenin

2021 ◽  
Vol 15 ◽  
Author(s):  
Rose Chesworth ◽  
Rashmi Gamage ◽  
Faheem Ullah ◽  
Sandra Sonego ◽  
Christopher Millington ◽  
...  
Keyword(s):  
Spatial Memory ◽  
Healthy Aging ◽  
Memory Function ◽  
Microglia Activation ◽  
Memory Recall ◽  
Suitable Model ◽  
Barnes Maze ◽  
Wild Type ◽  
Chronic Neuroinflammation ◽  
Age Related

Chronic neuroinflammation characterized by microglia reactivity is one of the main underlying processes in the initiation and progression of neurodegenerative diseases such as Alzheimer’s disease. This project characterized spatial memory during healthy aging and prolonged neuroinflammation in the chronic neuroinflammatory model, glial fibrillary acidic protein-interleukin 6 (GFAP-IL6). We investigated whether chronic treatment with the natural flavonoid, apigenin, could reduce microglia activation in the hippocampus and improve spatial memory. GFAP-IL6 transgenic and wild-type-like mice were fed with apigenin-enriched or control chow from 4 months of age and tested for spatial memory function at 6 and 22 months using the Barnes maze. Brain tissue was collected at 22 months to assess microgliosis and morphology using immunohistochemistry, stereology, and 3D single cell reconstruction. GFAP-IL6 mice showed age-dependent loss of spatial memory recall compared with wild-type-like mice. Chronic apigenin treatment decreased the number of Iba-1+ microglia in the hippocampus of GFAP-IL6 mice and changed microglial morphology. Apigenin did not reverse spatial memory recall impairment in GFAP-IL6 mice at 22 months of age. GFAP-IL6 mice may represent a suitable model for age-related neurodegenerative disease. Chronic apigenin supplementation significantly reduced microglia activation, but this did not correspond with spatial memory improvement in the Barnes Maze.

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