scholarly journals The Non-peptide Angiotensin-(1–7) Mimic AVE 0991 Attenuates Delayed Neurocognitive Recovery After Laparotomy by Reducing Neuroinflammation and Restoring Blood-Brain Barrier Integrity in Aged Rats

2021 ◽  
Vol 13 ◽  
Author(s):  
Xinning Mi ◽  
Yiyun Cao ◽  
Yue Li ◽  
Yitong Li ◽  
Jingshu Hong ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Blood Brain Barrier ◽  
Older Adult ◽  
Renin Angiotensin System ◽  
Receptor Expression ◽  
Adult Patients ◽  
Brain Barrier ◽  
Ang Ii ◽  
Matrix Metalloproteinase 3 ◽  
Blood Brain

Delayed neurocognitive recovery (dNCR) after surgery is a common postoperative complication in older adult patients. Our previous studies have demonstrated that cognitive impairment after surgery involves an increase in the brain renin-angiotensin system (RAS) activity, including overactivation of the angiotensin 2/angiotensin receptor-1 (Ang II/AT1) axis, which provokes the disruption of the hippocampal blood-brain barrier (BBB). Nevertheless, the potential role of the counter-regulatory RAS axis, the Ang-(1–7)/Mas pathway, in dNCR remains unknown. Using an aged rat model of dNCR, we dynamically investigated the activity of both axes of the RAS following laparotomy. AVE 0991, a nonpeptide analog of Ang-(1–7), was administered intranasally immediately after laparotomy. We found that the elevation of Ang II, induced by surgery was accompanied by a decrease of Ang-(1–7) in the hippocampus, but not in the circulation. Surgery also significantly downregulated hippocampal Mas receptor expression at 24 h postsurgery. Mas activation with intranasal AVE 0991 treatment significantly improved hippocampus-dependent learning and memory deficits induced by surgery. Furthermore, it attenuated hippocampal neuroinflammation, as shown by the decreased level of the microglial activation marker cluster of differentiation 11b (CD11b) and the decreased production of several inflammatory molecules. Along with these beneficial effects, the AVE 0991 treatment also alleviated the imbalance between matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), modulated the expression of occludin, and alleviated the IgG extravasation, thereby restoring the integrity of the BBB. In conclusion, these data indicate that activation of Mas by AVE 0991 attenuates dNCR after surgery by reducing neuroinflammation and restoring BBB integrity. Our findings suggest that the Ang-(1–7)/Mas pathway may be a novel therapeutic target for treating dNCR after surgery in older adult patients.

scholarly journals Mixed Vehicle Emissions Induces Angiotensin II and Cerebral Microvascular Angiotensin Receptor Expression in C57Bl/6 Mice and Promotes Alterations in Integrity in a Blood-Brain Barrier Coculture Model

2019 ◽  
Vol 170 (2) ◽  
pp. 525-535 ◽  
Author(s):  
Usa Suwannasual ◽  
JoAnn Lucero ◽  
Griffith Davis ◽  
Jacob D McDonald ◽  
Amie K Lund
Keyword(s):  
Blood Brain Barrier ◽  
Transforming Growth Factor ◽  
Cerebrovascular Disorders ◽  
Inhalation Exposure ◽  
Receptor Expression ◽  
Brain Barrier ◽  
Ang Ii ◽  
Blood Brain ◽  
At1 Antagonist ◽  
Cerebral Microvasculature

Abstract Exposure to traffic-generated pollution is associated with alterations in blood-brain barrier (BBB) integrity and exacerbation of cerebrovascular disorders. Angiotensin (Ang) II signaling through the Ang II type 1 (AT1) receptor is known to promote BBB disruption. We have previously reported that exposure to a mixture of gasoline and diesel vehicle engine emissions (MVE) mediates alterations in cerebral microvasculature of C57Bl/6 mice, which is exacerbated through consumption of a high-fat (HF) diet. Thus, we investigated the hypothesis that inhalation exposure to MVE results in altered central nervous system microvascular integrity mediated by Ang II-AT1 signaling. Three-month-old male C57Bl/6 mice were placed on an HF or low-fat diet and exposed via inhalation to either filtered air (FA) or MVE (100 μg/m3 PM) 6 h/d for 30 days. Exposure to HF+MVE resulted in a significant increase in plasma Ang II and expression of AT1 in the cerebral microvasculature. Results from a BBB coculture study showed that transendothelial electrical resistance was decreased, associated with reduced expression of claudin-5 and occludin when treated with plasma from MVE+HF animals. These effects were attenuated through pretreatment with the AT1 antagonist, Losartan. Our BBB coculture showed increased levels of astrocyte AT1 and decreased expression of aryl hydrocarbon receptor and glutathione peroxidase-1, associated with increased interleukin-6 and transforming growth factor-β in the astrocyte media, when treated with plasma from MVE-exposed groups. Our results indicate that inhalation exposure to traffic-generated pollutants results in altered BBB integrity, mediated through Ang II-AT1 signaling and inflammation, which is exacerbated by an HF diet.

Angiotensin generation in the brain: a re-evaluation

2018 ◽  
Vol 132 (8) ◽  
pp. 839-850 ◽  
Author(s):  
Estrellita Uijl ◽  
Liwei Ren ◽  
A.H. Jan Danser
Keyword(s):  
Blood Brain Barrier ◽  
Renin Angiotensin System ◽  
Brain Barrier ◽  
Ang Ii ◽  
Independent Manner ◽  
Neurogenic Hypertension ◽  
Local Synthesis ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
The Brain

The existence of a so-called brain renin-angiotensin system (RAS) is controversial. Given the presence of the blood–brain barrier, angiotensin generation in the brain, if occurring, should depend on local synthesis of renin and angiotensinogen. Yet, although initially brain-selective expression of intracellular renin was reported, data in intracellular renin knockout animals argue against a role for this renin in angiotensin generation. Moreover, renin levels in brain tissue at most represented renin in trapped blood. Additionally, in neurogenic hypertension brain prorenin up-regulation has been claimed, which would generate angiotensin following its binding to the (pro)renin receptor. However, recent studies reported no evidence for prorenin expression in the brain, nor for its selective up-regulation in neurogenic hypertension, and the (pro)renin receptor rather displays RAS-unrelated functions. Finally, although angiotensinogen mRNA is detectable in the brain, brain angiotensinogen protein levels are low, and even these low levels might be an overestimation due to assay artefacts. Taken together, independent angiotensin generation in the brain is unlikely. Indeed, brain angiotensin levels are extremely low, with angiotensin (Ang) I levels corresponding to the small amounts of Ang I in trapped blood plasma, and Ang II levels at most representing Ang II bound to (vascular) brain Ang II type 1 receptors. This review concludes with a unifying concept proposing the blood origin of angiotensin in the brain, possibly resulting in increased levels following blood–brain barrier disruption (e.g. due to hypertension), and suggesting that interfering with either intracellular renin or the (pro)renin receptor has consequences in an RAS-independent manner.

scholarly journals Blood-brain barrier permeability is regulated by matrix metalloproteinase-3 via the ERK signaling pathway

2020 ◽  
Author(s):  
Qin Zhang ◽  
Mei Zheng ◽  
Cristian E Betancourt ◽  
Lifeng Liu ◽  
Albert Sitikov ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Signaling Pathway ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Erk Signaling ◽  
Anesthesia Induction ◽  
Matrix Metalloproteinase 3 ◽  
Blood Brain ◽  
Bbb Permeability

Abstract Background The blood–brain barrier (BBB) regulates the exchange of molecules between the brain and peripheral blood and is composed primarily of microvascular endothelial cells (BMVECs), which form the lining of cerebral blood vessels and are linked via tight junctions (TJs). The BBB is regulated by components of the extracellular matrix (ECM), and matrix metalloproteinase 3 (MMP3) remodels the basal lamina of the ECM, which forms part of the BBB. Thus, we investigated whether MMP3 modulates BBB permeability. Methods Experiments included in-vivo assessments of isoflurane anesthesia and dye extravasation from brain in wild-type (WT) and MMP3-deficient (MMP3-KO) mice, as well as in-vitro assessments of the integrity of monolayers of WT and MMP3-KO BMVECs (via measurements of transendothelial electrical resistance [TEER] and transwell assays in a co-culture of BMVECs with astrocytes and the expression of junction proteins. Results Compared to assessments in WT mice, measurements of isoflurane usage and anesthesia induction time were higher in MMP3-KO mice and lower in WT mice that had been treated with MMP3 (WT + MMP3), while anesthesia emergence times were shorter in MMP3-KO mice and longer in WT + MMP3 mice than in WT mice. Extravasation of systemically administered dyes was also lower in MMP3-KO mouse brains, and higher in WT + MMP3 mouse brains, than in the brains of WT mice, and the results from both TEER and transwell assays indicated that MMP3 deficiency (or inhibition) increased, while MMP3 upregulation reduced, barrier integrity in either BMVEC monolayers or the co-culture. MMP3 deficiency also increased the abundance of TJ and VE-cadherin proteins in BMVECs, and the protein abundance declined when MMP3 activity was upregulated in BMVECs, but not when the cells were treated with an inhibitor of extracellular signal related kinase (ERK). Conclusion MMP3 increases BBB permeability by upregulating the ERK signaling pathway, which subsequently reduces TJ and VE-cadherin proteins abundance in BMVECs. Collectively, these observations suggest that MMP3 could be therapeutically targeted to manipulate BBB permeability and treat neurological disease.

Increased serum matrix metalloproteinase-9 in neuromyelitis optica: Implication of disruption of blood–brain barrier

2011 ◽  
Vol 236 (1-2) ◽  
pp. 81-86 ◽  
Author(s):  
Takafumi Hosokawa ◽  
Hideto Nakajima ◽  
Yoshimitsu Doi ◽  
Masakazu Sugino ◽  
Fumiharu Kimura ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Blood Brain Barrier ◽  
Neuromyelitis Optica ◽  
Matrix Metalloproteinase 9 ◽  
Brain Barrier ◽  
Blood Brain ◽  
Metalloproteinase 9

scholarly journals Impact of the Renin–Angiotensin System on the Endothelium in Vascular Dementia: Unresolved Issues and Future Perspectives

2020 ◽  
Vol 21 (12) ◽  
pp. 4268 ◽  
Author(s):  
Fatima Y. Noureddine ◽  
Raffaele Altara ◽  
Fan Fan ◽  
Andriy Yabluchanskiy ◽  
George W. Booz ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Dementia ◽  
Blood Brain Barrier ◽  
Renin Angiotensin System ◽  
Brain Barrier ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Blood Brain ◽  
Body Tissues ◽  
The Brain

The effects of the renin–angiotensin system (RAS) surpass the renal and cardiovascular systems to encompass other body tissues and organs, including the brain. Angiotensin II (Ang II), the most potent mediator of RAS in the brain, contributes to vascular dementia via different mechanisms, including neuronal homeostasis disruption, vascular remodeling, and endothelial dysfunction caused by increased inflammation and oxidative stress. Other RAS components of emerging significance at the level of the blood–brain barrier include angiotensin-converting enzyme 2 (ACE2), Ang(1–7), and the AT2, Mas, and AT4 receptors. The various angiotensin hormones perform complex actions on brain endothelial cells and pericytes through specific receptors that have either detrimental or beneficial actions. Increasing evidence indicates that the ACE2/Ang(1–7)/Mas axis constitutes a protective arm of RAS on the blood–brain barrier. This review provides an update of studies assessing the different effects of angiotensins on cerebral endothelial cells. The involved signaling pathways are presented and help highlight the potential pharmacological targets for the management of cognitive and behavioral dysfunctions associated with vascular dementia.

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