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Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension.

ABSTRACT: Hypertension is a leading risk factor for dementia, but the mechanisms underlying its damaging effects on the brain are poorly understood. Due to a lack of energy reserves, the brain relies on continuous delivery of blood flow to its active regions in accordance with their dynamic metabolic needs. Hypertension disrupts these vital regulatory mechanisms, leading to the neuronal dysfunction and damage underlying cognitive impairment. Elucidating the cellular bases of these impairments is essential for developing new therapies. Perivascular macrophages (PVMs) represent a distinct population of resident brain macrophages that serves key homeostatic roles but also has the potential to generate large amounts of reactive oxygen species (ROS). Here, we report that PVMs are critical in driving the alterations in neurovascular regulation and attendant cognitive impairment in mouse models of hypertension. This effect was mediated by an increase in blood-brain barrier permeability that allowed angiotensin II to enter the perivascular space and activate angiotensin type 1 receptors in PVMs, leading to production of ROS through the superoxide-producing enzyme NOX2. These findings unveil a pathogenic role of PVMs in the neurovascular and cognitive dysfunction associated with hypertension and identify these cells as a putative therapeutic target for diseases associated with cerebrovascular oxidative stress.

SUBMITTER: Faraco G

PROVIDER: S-EPMC5127678 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension.

Faraco Giuseppe G Sugiyama Yukio Y Lane Diane D Garcia-Bonilla Lidia L Chang Haejoo H Santisteban Monica M MM Racchumi Gianfranco G Murphy Michelle M Van Rooijen Nico N Anrather Joseph J Iadecola Costantino C

The Journal of clinical investigation 20161114 12

Hypertension is a leading risk factor for dementia, but the mechanisms underlying its damaging effects on the brain are poorly understood. Due to a lack of energy reserves, the brain relies on continuous delivery of blood flow to its active regions in accordance with their dynamic metabolic needs. Hypertension disrupts these vital regulatory mechanisms, leading to the neuronal dysfunction and damage underlying cognitive impairment. Elucidating the cellular bases of these impairments is essential ...[more]

PMID: 27841763

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Project description: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 Angiotensin II infusion is associated with increased permeability of the blood-brain barrier (BBB), chronic activation of microglia and myelin loss. 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/wtxThy1 yfp/0 reporter mice were infused for 12 weeks with Angiotensin II or saline and subgroups were treated with PLX5622, a highly selective CSF1R tyrosine kinase inhibitor. Systolic blood pressure (SBP) was measured via tail-cuff. Short- and long-term spatial memory was assessed during an Object Location task and a Morris Water Maze task (MWM). Microglia depletion efficacy was assessed by flow cytometry and immunohistochemistry. BBB leakages, microglia phenotype and myelin integrity were assessed by 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, and partly prevented in Ang II mice treated with PLX5622. Histological and flow cytometry analysis revealed almost complete ablation of microglia and a 60% depletion of brain resident perivascular macrophages upon CSF1R inhibition. Number and size of BBB leakages were increased in Ang II hypertensive mice, but not altered by PLX5622 treatment. Microglia acquired a pro-inflammatory phenotype at the site of BBB leakages in both Saline and Ang II mice and were successfully depleted by PLX5622. There was however no significant change in myelin integrity at the site of leakages. Conclusion: Our results show that depletion of microglia and PVMs, by CSF1R inhibition prevents short-term memory impairment in Ang II induced hypertensive mice. We suggest this beneficial effect is mediated by the major decrease of pro-inflammatory microglia within BBB leakages. This novel finding supports the critical role of brain immune cells in the pathogenesis of hypertension-related cognitive impairment. An adequate modulation of microglia /PVM density and phenotype may constitute a relevant approach to prevent and/or limit the progression of vascular cognitive impairment.

Dataset Information

Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension.

Publications

Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension.

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