Structural and functional brain alterations in a murine model of Angiotensin <scp>II</scp>‐induced hypertension

Meißner, Anja; Minnerup, Jens; Sòria, Guadalupe; Planas, Anna M.

doi:10.1111/jnc.13905

Cited by 40 publications

(54 citation statements)

References 63 publications

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“…Indeed, there is evidence that circulating leucocytes can infiltrate the CNS. In one study, Ang II-induced hypertension resulted in the accumulation of CD3 + T cells into the cerebral artery wall, suggesting that the vasculature was deleteriously affected (Meissner et al 2017). A more conclusive study showed that spontaneously hypertensive rats with reconstituted bone marrow from normotensive Wistar-Kyoto rats had decreased blood pressure and inflammation (Santisteban et al 2015).…”

Section: Blood-brain Barrier Disruption In Hypertensionmentioning

confidence: 99%

The role of the blood–brain barrier in hypertension

Setiadi

Korim

Elsaafien

et al. 2017

Experimental Physiology

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What is the topic of this review? This review highlights the importance of the blood-brain barrier in the context of diseases involving autonomic dysfunction, such as hypertension and heart failure. What advances does it highlight? It highlights the potential role of pro-inflammatory cytokines, leucocytes and angiotensin II in disrupting the blood-brain barrier in cardiovascular diseases. Advances are highlighted in our understanding of neurovascular unit cells, astrocytes and microglia, with a specific emphasis on their pathogenic roles within the brain. The blood-brain barrier (BBB) is a crucial barrier that provides both metabolic and physical protection to an immune-privileged CNS. The BBB has been shown to be disrupted in hypertension. This review addresses the importance of the BBB in maintaining homeostasis in the context of diseases related to autonomic dysfunction, such as hypertension. We highlight the potentially important roles of the immune system and neurovascular unit in the maintenance of the BBB, whereby dysregulation may lead to autonomic dysfunction in diseases such as heart failure and hypertension. Circulating leucocytes and factors such as angiotensin II and pro-inflammatory cytokines are thought ultimately to downregulate endothelial tight junction proteins that are a crucial component of the BBB. The specific mechanisms underlying BBB disruption and their role in contributing to autonomic dysfunction are not yet fully understood but are a growing area of interest. A greater understanding of these systems and advances in our knowledge of the molecular mechanisms causing BBB disruption will allow for the development of future therapeutic interventions in the treatment of autonomic imbalance associated with diseases such as heart failure and hypertension.

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Section: Blood-brain Barrier Disruption In Hypertensionmentioning

confidence: 99%

The role of the blood–brain barrier in hypertension

Setiadi

Korim

Elsaafien

et al. 2017

Experimental Physiology

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“…The use of Angiotensin II (Ang II) infusion has been previously associated with hypertension-induced cerebrovascular dysfunction including increased BBB permeability and neuroinflammation [32][33][34]. We have also shown earlier the presence of activated microglia in association with BBB leakages and short-term memory impairment in a prolonged Ang II infusion (12 weeks) model [35].…”

Section: Introductionmentioning

confidence: 71%

“…An impaired BBB permeability induced by chronic hypertension is associated with microglia activation and short-term memory impairment [32][33][34][35]. In the present study we aimed to determine the contribution of microglia cells to hypertension-induced cognitive impairment using a pharmacological depletion approach.…”

Section: Discussionmentioning

confidence: 98%

Pharmacological depletion of microglia prevents vascular cognitive impairment in Ang II-induced hypertension

Kerkhofs

Hagen

Milanova

et al. 2020

Preprint

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Rationale: Hypertension is a major risk factor for cerebral small vessel disease, the most prevalent cause of vascular cognitive impairment. As we have shown, hypertension induced by a prolonged Ang II infusion is associated with increased permeability of the blood-brain barrier (BBB) and chronic activation of microglia. In this study we therefore aim to determine the contribution of microglia to hypertension-induced cognitive impairment in an experimental hypertension model by a pharmacological depletion approach.Methods: For this study, adult Cx3Cr1 gfp/wt xThy1 yfp/0 reporter mice were infused for 12 weeks with Angiotensin II or saline and subgroups were treated with PLX5622, a highly selective CSF-1R inhibitor. Systolic blood pressure (SBP) was measured via tail-cuff. Short-and long-term spatial memory were assessed during an Object Location task and a Morris Water Maze task (MWM). At the end of the study, microglia depletion efficacy and BBB leakages were assessed using flow cytometry and immunohistochemistry.Results: SBP, heart weight and carotid pulsatility were increased by Ang II and were not affected by PLX5622. Short-term memory was significantly impaired in Ang II hypertensive mice, but not in Ang II mice treated with PLX5622. Histological and flow cytometry analyses revealed almost complete ablation of microglia upon CSF1R inhibition, while brain resident perivascular macrophages, were reduced by 60%. Number and size of BBB leakages were increased in Ang II hypertensive mice, but not altered by PLX5622 treatment. Conclusion:Our results show that depletion of microglia, and less so PVMs, by CSF1R inhibition prevents short-term memory impairment in Ang II induced hypertensive mice. This novel finding supports the critical role of brain immune cells, and most in particular microglia, in the pathogenesis of hypertension-related cognitive impairment. VCI vascular cognitive impairment;WMH white matter hyperintensities.

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“…However, there is no reliable treatment for CSVD . CSVD is characterized by white matter hyperintensities, cognitive impairment, cerebral microbleeds, and cerebrovascular injury in patients . BBB leakage is considered to be the initiating factor of CSVD and is related to the severity of the disease …”

Section: Introductionmentioning

confidence: 99%

“…3,4 CSVD is characterized by white matter hyperintensities, cognitive impairment, cerebral microbleeds, and cerebrovascular injury in patients. 1,5,6 BBB leakage is considered to be the initiating factor of CSVD and is related to the severity of the disease. 7 The blood-brain barrier (BBB) is formed by the endothelium, astroglia, pericytes, and basal lamina.…”

Section: Introductionmentioning

confidence: 99%

Nicotinamide riboside rescues angiotensin II–induced cerebral small vessel disease in mice

Chen

Wang

et al. 2020

CNS Neurosci Ther

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Aims Hypertension is a leading cause of cerebral small vessel disease (CSVD). Currently, treatments for CSVD are limited. Nicotinamide riboside (NR) can protect against vascular injury and cognitive impairment in neurodegenerative diseases. In this study, the protective effects of NR against angiotensin ‐ (Ang ‐)–induced CSVD were evaluated. Methods To explore the effects of NR in CSVD, C57BL/6 mice were infused with Ang ‐, and NR was added to the food of the mice for 28 days. Then, short‐term memory, blood‐brain barrier (BBB) integrity, and endothelial function were detected. Arteriole injury and glial activation were also evaluated. Results Our data showed that mice infused with Ang ‐ exhibited decreased short‐term memory function and BBB leakage due to decreased claudin‐5 expression and increased caveolae‐mediated endocytosis after 28 days. Furthermore, Ang ‐ decreased the expression of α‐smooth muscle actin (α‐SMA) and increased the expression of proliferating cell nuclear antigen (PCNA) in arterioles and decreased the expression of neurofilament 200 (NF200) and myelin basic protein (MBP) in the white matter. These CSVD‐related damages induced by Ang ‐ were inhibited by NR administration. Moreover, NR administration significantly reduced glial activation around the vessels. Conclusion Our results indicated that NR administration alleviated Ang ‐–induced CSVD by protecting BBB integrity, vascular remodeling, neuroinflammation, and white matter injury (WMI)–associated cognitive impairment.

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Structural and functional brain alterations in a murine model of Angiotensin II‐induced hypertension

Cited by 40 publications

References 63 publications

The role of the blood–brain barrier in hypertension

The role of the blood–brain barrier in hypertension

Pharmacological depletion of microglia prevents vascular cognitive impairment in Ang II-induced hypertension

Nicotinamide riboside rescues angiotensin II–induced cerebral small vessel disease in mice

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