Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension
Giuseppe Faraco, Yukio Sugiyama, Diane Lane, Lidia Garcia-Bonilla, Haejoo Chang, Monica M. Santisteban, Gianfranco Racchumi, Michelle Murphy, Nico Van Rooijen, Joseph Anrather, Costantino Iadecola
Giuseppe Faraco, Yukio Sugiyama, Diane Lane, Lidia Garcia-Bonilla, Haejoo Chang, Monica M. Santisteban, Gianfranco Racchumi, Michelle Murphy, Nico Van Rooijen, Joseph Anrather, Costantino Iadecola
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Research Article Neuroscience Vascular biology

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.

Authors

Giuseppe Faraco, Yukio Sugiyama, Diane Lane, Lidia Garcia-Bonilla, Haejoo Chang, Monica M. Santisteban, Gianfranco Racchumi, Michelle Murphy, Nico Van Rooijen, Joseph Anrather, Costantino Iadecola

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Figure 2

Slow pressor ANGII disrupts the BBB, leading to ANGII entry into the perivascular space and PVMs.

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Slow pressor ANGII disrupts the BBB, leading to ANGII entry into the per...
(A) Slow pressor ANGII gradually increases systolic blood pressure measured by tail-cuff plethysmography. *P < 0.05 vs. vehicle (Veh); n = 12–17 (2-way ANOVA and Bonferroni’s test). (B) ANGII plasma levels are increased after 2 weeks of ANGII administration. *P < 0.05 vs. Veh; n = 8–9 (Student’s t test). (C) Slow pressor hypertension but not acute i.v. ANGII administration increases BBB permeability to FITC-dextran (MW 3 kDa). *P < 0.05 vs. Veh; n = 5–7 (Student’s t test). (D) Confocal microscopy showing immunofluorescence labeling of biotinylated ANGII around cerebral blood vessels and in association with PVMs in mice treated with ANGII for 14 days but not in saline-treated mice (scale bar: 25 μm). (E) Orthogonal views (XY, XZ, YZ) illustrating colocalization of biotin-ANGII (green) and CD206 (blue). (F) Biotin-ANGII is associated with PVMs in mice treated with ANGII for 14 days but not in saline-treated mice or in mice acutely infused with ANGII. *P < 0.05 vs. Veh and acute ANGII; n = 3–4 per group; 86 ± 9 PVMs per animal (1-way ANOVA and Tukey’s test). (G) Electron micrographs of cortical arterioles showing immunoperoxidase labeling of biotinylated ANGII tracking along tight junctions (arrows) and reaching perivascular space (arrowheads) in mice treated with ANGII for 14 days (right) but not in saline-treated mice (left). Scale bar: 100 nm. PVM, perivascular macrophage; EC, endothelial cell; VSMC, vascular smooth muscle cells; BM, basement membrane.